Advanced searches left 3/3
Search only database of 8 mil and more summaries

SMN1

Summarized by PlexPage
Last Updated: 02 July 2021

* If you want to update the article please login/register

General | Latest Info

SMN1

Identifiers
AliasesSMN1 , BCD541, GEMIN1, SMNT, T-BCD541, TDRD16A, survival of motor neuron 1, telomeric, survival motor neuron 1, telomeric, SMA1, SMA4, SMA@, SMA2, SMA, SMA3, SMN
External IDsOMIM: 600354 MGI: 109257 HomoloGene: 292 GeneCards: SMN1
Orthologs
Wikidata
View/Edit HumanView/Edit Mouse
Protein SMN1 PDB 1g5v.png "Protein SMN1 PDB 1g5v.png", by Emw, licensed under CC BY-SA 3.0

Spinal Muscular Atrophy is caused by a mutation in survival motor neuron 1 Gene. This gene is responsible for producing survival motor neuron protein, which maintains health and normal function of motor neurons. In individuals with Spinal Muscular Atrophy, both copies of SMN1 Gene are mutate, leading to decreased production of SMN protein. Without a proper level of SMN protein, motor neurons in the spinal cord will be lose, preventing muscles from receiving proper signals from the brain. Spinal Muscular Atrophy affects everyone differently, and it is important to note that symptoms can vary greatly according to age of onset and disease severity. Individuals may experience progressive muscle weakness in muscles closest to the center of the body, such as shoulders, thighs, and pelvis. These muscles enable activities such as head control / movement, sitting up, crawling, and walking. Breathing and swallowing may also be affect. It is believed that Spinal Muscular Atrophy does not affect neurons responsible for cognition, which is a mental process through which we gain knowledge and understanding through thought, experience, and senses. According to one study, children and adolescents with Spinal Muscular Atrophy have normal intelligence, with IQs in the standard range. For school - age children, special accommodation may be needed to help maintain cognitive and intellectual engagement. All individuals with Spinal Muscular Atrophy have at least one backup Gene, known as SMN2. Smn2 Gene has a similar structure to SMN1, but only a small amount of SMN protein it produces is fully functional. This low level of SMN protein is not effective enough to sustain survival of motor neurons in CNS. The number of SMN2 genes may vary, and higher SMN2 copy number is associated with less - severe symptoms of Spinal Muscular Atrophy. Nevertheless, disease has a wide range of symptoms and it is difficult to predict severity based on the number of SMN2 copies alone. Thus, experts recommend that care decisions be made based on individuals ' functional ability and not on SMN2 copy number alone. The discovery of this backup gene provides a unique opportunity for development of potential therapies that may help SMN2 Gene produce more SMN protein.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Gene

Human SMN1 and SMN2 gene promoters are nearly identical in sequence and activity. The principal transcriptional initiation site for SMN genes is located 163 base pairs upstream of the translation initiation site. The second transcriptional initiation site has been mapped to 246 base pairs upstream and appears to be in used during fetal development. Approximately 150 base - pair regions upstream of translation initiation site contain sequences necessary for minimal promoter activity, although regulatory sequences relevant to SMN gene expression may be present as far as 4. 6 kb upstream of transcription initiation site. Smn expression varies in different tissue types and likely decreases with development from embryonic to early postnatal stages. Smn promoter activity has also been demonstrated to decrease with cellular differentiation. It has been shown that SMN promoter contains binding sites for and binds cAMP - response element binding protein, Sp family of proteins, and interferon regulatory factor, all of which can modulate promoter activity. In addition, it has been demonstrated that SMN promoter IS associated with histone deacetylase 1 and 2 proteins, which likely modulate histone acetylation state at SMN promoter, thereby playing a role in determining activity of the promoter during development. More work IS needed to dissect deoxyribonucleic acid - binding proteins and epigenetic modifications that are most critical in regulating SMN gene expression.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Spinal muscular atrophy

Spinal muscular atrophy is a pan - ethnic, autosomal recessive disease caused by loss of function of SMN1 Gene. In over 95% of cases, patients are missing both copies of SMN1 Gene. The disease is characterized by degeneration of alpha motor neurons of spinal cord anterior horn cells, leading to progressive symmetric weakness, atrophy of proximal voluntary muscles and early death. The age of onset can be anywhere on continuum from the prenatal period to adulthood. Sma 0 represents the most severe form. Infants are born with severe hypotonia and joint contractures; no motor milestones are achieved and patients die before 6 months of age. Sma I has age onset in the first six months of life. These cases are associated with death, usually at age 2 and lack of development of motor skills. Sma II has an age of onset between 3 and 15 months; patients may be able to sit independently. Intelligence is not affect. Life expectancy may vary from early childhood to early adulthood. Sma III has age onset after 18 months of age and as late as adolescence; patients may learn to stand and to walk short distances. These patients may have a normal lifespan. Sma IV is an adult - onset disorder of muscle weakness; life span is not shorten. Most patients, regardless of the severity of disease, have deletion of both SMN1 copies. Patients with later - onset disease usually have three or more copies of SMN2, which encodes small amount of residual protein and lessens severity of symptoms. However, other factors besides SMN2 copy number may affect phenotype, and therefore severity of disease may not be able to be accurately predicted in all patients based on genotype. For information about carrier frequency and residual risk, please see the residual Risk Table.


Results

Asp44 is in exon 2a of SMN1, and involved in SMA - link Asp44Val missense mutation, which involves substitution of Asp44s charge side chain by Val44s hydrophobic side chain. Of extraordinary functional significance is that SMNs Gemin2 binding activity is totally suppressed by D44V mutation in SMN1. Moreover, D44V SMN mutant s snRNP assembly activity is lower than that of wild - type SMN. In snRNP assembly, one important participant is SMN - Gemin2 complex, whose core structure was determined by solution - state nuclear magnetic resonance spectroscopy. In computational analysis of the SMN - Gemin2 complex, three salt bridges were identified between bury side chains of two charged residues, ie, SMNs Asp44 and Gemin2s Arg213, distance between geometric centers of two oppositely charge groups was 3. 50 0. 23. Specifically, for side chain charge groups of SMNs Asp44 and Gemin2s Arg213, distance distribution for all 32 NMR structure models is 8. 33 2. 55 for O 2 - N 2 nucleus pair, and 8. 71 1. 82 for O 2 - N 1 nucleus pair, and 8. 08 3. 02 for O 1 - N 2 nucleus pair, and 8. 59 2. 27 for O 1 - N 1 nucleus pair. These distance distributions argue against the existence of Asp44 - Arg213 salt bride, although three were computationally identified in NMR ensemble. Yet, in subsequent analysis of experimental NMR restraints deposit in BMRB database, set of chemical shift assignments were found to be missing for group of crucial side chain nuclei, including C of SMNs Asp44 and C, all side chain nitrogen nuclei and all nitrogen - bond side chain hydrogen nuclei of Gemin2s Arg213. Missing assignments of those chemical shifts increase the degree of geometric freedom for side chains in experimental structure determation, and result in inadequate accuracy of geometric definition of Asp44s and Arg213s side chains in NMR ensemble. Take together, it is conceivable that buried side chains of SMNs Asp44 and Gemin2s Arg213 form salt bridge, which constitutes favourable electrostatic energy contribution to SMN - Gemin2's complex structural stability, and highlights functionally indispensable roles of two residue charge side chains, considering experimental observation that SMN - Gemin2 binding is abrogated by D44V mutation, resulting in functionally deficient SMA - link D44V SMN mutant. In comparison, Lys41 is positively charge residue and also neighbouring residue of Asp44. Functionally different to SMA - link D44V mutation, Lys41Ala mutation does not affect SMN - Gemin2 binding.


Carrier (Heterozygote) Detection

In parents of children with molecularly confirmed SMA. If child is confirmed to have exon 7 deleted from both copies of SMN1, first perform SMN1 dosage analysis on both parents: If child is confirmed to have exon 7 deleted from one copy of SMN1 and intragenic pathogenic variant in other copy of SMN1, first perform SMN1 dosage analysis on both parents: in parents of deceased child with suspected but not molecularly confirm SMA. As first step, attempt to test any available tissue samples, such as muscle biopsies and blood spots from newborn screening, as these samples can often provide enough DNA for molecular genetic testing. If DNA is not available, perform SMN1 dosage analysis on both parents:

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Causes/Inheritance

Most common types of SMA are associated with mutation in the SMN1 gene, which is located on chromosome 5. About 95 percent of people with SMA have mutations where a section of SMN1 gene is deleted in both copies of the gene. The Smn1 gene provides instructions for making Survival Motor Neuron protein that is found in all parts of the body, and exists at high levels in the spinal cord. This protein is important for maintaining the function of motor Neuron cells. As result of mutations in SMN1 gene, little or no SMN protein is make. Research findings indicate that motor neurons are particularly vulnerable to shortage of SMN protein and die prematurely. In humans, there is a second gene called SMN2. Some people have three or more copies of SMN2 gene. Like the SMN1 gene, SMN2 genes provide instructions for making SMN protein. Extra SMN2 genes can help provide some of the SMN protein. But fewer full - size SMN proteins are produced from SMN2 genes compared to SMN1 gene. In these people, SMA symptoms are much less severe. Finkel type SMA is associated with mutations in VAPB gene located on chromosome 20. This gene contains instructions to produce VAPB protein that is associated with membrane that surround endoplasmatic reticulum, which is where newly - made proteins acquire their three - dimentional structure and are prepared to be transported within cell or to cell surface. The mutation causes amino acid proline to be replaced with amino acid serine at position 56. This causes amyothrophic lateral sclerosis in some people and SMA in others. Mutate proteins cannot activate unfold protein response, resulting in protein aggregates that lead to cell death. Motor neurons are particularly vulnerable to cell death, caused by protein aggregates. The Dync1h1 gene - located on chromosome 14 - provides instructions to make protein that is part of a complex group of proteins, know as dynein, which are found in cytoplasm. In neurons, dynein moves proteins and other cellular materials away from junctions between neurons to the center of the cell, facilitating passage of chemical messages from one neuron to another. Mutations in DYNC1H1 gene cause form of SMA called SMA - lead, which primarily affects legs. As a result, movement of proteins and cellular materials is impaired, resulting in a decrease in chemical messaging between neurons that control muscle movement. Mutations in UBA1 gene cause X - link infantile SMA condition. This gene, located on the X chromosome, is responsible for making an ubiquitin - activating enzyme called E1 involved in degradation of proteins within cells. Protein degradation is essential to remove damage or unnecessary proteins and to maintain normal function of cells. At least three mutations in the UBA1 gene have been find. Two of them are thought to lead to enzymes with impaired function.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

About SMA

Smn1 Gene provides instructions for making survival motor neuron protein. Smn protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called SMN complex, which is important for maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and part of the brain that is connected to the spinal cord. Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense, which allows the body to move. In cells, SMN complex plays an important role in processing molecules called messenger RNA, which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble cellular machinery needed to process pre - mRNA. The Smn complex is also important for development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for transmission of impulses between neurons and from neurons to muscles. A small amount of SMN protein is produced from a gene similar to SMN1 called SMN2. Several different versions of SMN protein are produced from SMN2 Gene, but only one version is functional; other versions are smaller and quickly broken down.


Spinal muscular atrophy

Many mutations in the SMN1 gene have been found to cause spinal muscular atrophy. This condition is characterized by loss of motor neurons that leads to weakness and wasting in muscles used for movement that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among types. About 95 percent of individuals with spinal muscular atrophy have mutations that delete piece of SMN1 gene in both copies of gene in each cell. As a result, SMN protein production is impair. In about 5 percent of people with this disorder, one copy of the SMN1 gene is missing a section, and the other copy has different kinds of mutation that disrupt production or function of SMN protein. Researchers suggest that shortage of SMN protein leads to inefficient assembly of machinery needed to process pre - mRNA. Lack of mature mRNA, and subsequently proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. Loss of motor neurons leads to signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to reduction in amount of SMN protein. Some research findings indicate that shortage of this protein impairs formation and function of axons and dendrites, leading to death of motor neurons. Typically, people have two copies of SMN1 gene and one to two copies of SMN2 gene in each cell. However, number of copies of SMN2 gene varies, with some people having up to eight copies. Multiple copies of SMN2 gene are usually associated with less severe features of condition that develop later in life. A small amount of SMN protein produced by SMN2 genes can help make up for protein deficiency caused by SMN1 gene mutations. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.


Results

The critical function that is affected by SMA is snRNP assembly, and it is well known that snRNP biogenesis pathway involves four steps: SMN oligomerization, SMN interaction with Gemin proteins, SMN binding to Sm proteins of snRNPs, which are key constituents of spliceosomes, SMN - coilin interaction in Cajal bodies, nuclear organelles involve in maturation of spliceosomal snRNPs. In computational analysis here, residue is defined as potentially important if its side chain is found to be involved in salt bridge or hydrogen bond, or its SASA is smaller than 30% of its standard SASA value. These potentially important SMN residues are listed in the first two columns of Table in S2 File. Among them, only seven residues were found to be involved in SMA - link point mutations of SMN1, as highlighted with white texts and black backgrounds in Table in S2 File.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

SMN1, SMN2

Smn2 copy number in SMA samples. Distribution of SMN2 copy number in SMA patient samples. Relationship between SMN2 copy number and disease severity in SMN1 - delete SMA samples. Each bar represents Clinical grade of SMA. Distribution of SMN2 copy numbers within each clinical grade is shown within each bar. Smn1 and SMN2 copy numbers in non - SMA samples. Each bar represents copy number for SMN1 in cohort of non - SMA samples. Distribution of SMN2 copy numbers within each SMN1 copy number is shown within each bar. None of the samples in our cohort contain 4 copies of SMN2.


Results

Distributions of SMN genotypes in unaffected individuals are shown in Table 1. Smn2 copy number and SMN1 copy number correlate inversely in the general population. Smn2 copy number decreased to one or zero copies in 11 of 13 individuals with three or four copies of SMN1, whereas only 71 of 164 individuals with 2 SMN1 copies had one or zero SMN2 copies. There was notable tendency for SMA type I carriers to have fewer SMN2 copies, compared to type II and type III carriers. While only three of 177 noncarriers with two or more SMN1 copies had three SMN2 copies, SMN2 copy number was increased to three or four copies in 19 of 109 carriers with SMN1 deletion / conversion mutations. Distribution of SMN genotype in 32 SMA patients is as followed with genotype expressed as: among 16 type patients, three were 0: 1 and 13 were 0: 2; single type I - II patient was 0: 2; among eight type II patients, one was 0: 2 and seven were 0: 3 and one was 0. 4; and one patient with very mild adult - onset SMA was 0: 4. Smn2 copy numbers correlate inversely with disease severity.


Methods

Forty - four patients were referred from Clinical Genetics out - patient clinics. Sma Diagnosis was according to criteria defined by the International SMA Consortium. Ten healthy individuals were used as control group, for normalization of Real - Time quantification data results within each run. Write informed consent were take from all subjects or from their guardians. Genomic DNA was extracted from peripheral blood of SMA patients and controls according to standard methods. All patients had homozygous deletion of exon 7 of SMN1 gene, which was determined by PCR - RFLP. Both exon 5 deletion of NAIP gene and Copy Number variations of exon 7 of SMN2 gene were also estimate.


Discussion

We established a new array dPCR SMN1 and SMN2 copy number assay that accurately measures copy numbers in SMA as well as in non - SMA DNA samples isolated from whole blood cells and cell lines derived from fibroblasts and lymphoblasts. Dpcr - derive SMN1 and SMN2 copy numbers match those found in reference standards used by diagnostic laboratory and in a limited number of cases using microdroplet dPCR. Smn2 copy numbers in SMA DNA samples were concordant with those results measured by TaqMan qPCR at low SMN2 copy numbers but concordance was not as strong at higher SMN2 copy numbers. The majority of dPCR / TaqMan qPCR mismatches occur at higher SMN2 copy numbers where TaqMan qPCR assay cannot easily distinguish unit differences. Array dPCR detects unit differences in SMN2 copy number over a wide range of SMN2 copy numbers similar to droplet dPCR. Because of this wide range of detection, dPCR can be very useful in accurately quantifying SMN2 copy numbers in patients with milder forms of SMA, that is, type III SMA, who generally have higher SMN2 copy numbers. Reliability of array dPCR assays was determined by comparing coefficients of variation for all samples with the same copy number. Our array dPCR results had 1. 6 - 3. 7% CV for SMN1 and 2. 1 - 3. 7% CV for SMN2. In contrast, TaqMan qPCR assay show 5. 2 - 9. 7% CV for SMN1 and 0. 8 - 7. 6% CV for SMN2. Greater reliability of array dPCR assay when compared against TaqMan qPCR assays is the result of random distribution of template DNA molecules within 20 000 partitions in microfluidic dPCR array. Using array dPCR, we have confirmed very strong inverse correlation between SMN2 copy number and disease severity in our SMA patient samples. Numerous previous studies also document a similar relationship between SMN2 copy number and SMA disease severity. Smn2 copy number is associated with many measures of SMA phenotype severity including gross motor function, force vital capacity, muscle mass, and denervation. Many current and future clinical trials for SMA will use these outcomes measures along with changes in SMN expression to gauge efficacy. Because SMN2 copy number is the defining criteria of eligibility for many SMA clinical trials, accurate and reliable measurements will continue to be essential to clinical research. In some cases, within our pool of SMA samples, there were SMA patients with low SMN2 copy numbers exhibiting milder phenotype. A rare variant in SMN2, SMN2 C. 859g > C, may explain this finding as it results in partial rescue of truncated, exon 7 exclude, transcript that characterizes most of the mRNA generated from SMN2. Array dPCR will aid in identification of cases having mismatches from expected genotype - phenotype relationship. Identifying such mismatches could lead to identification of potential complementing mutations in SMN2 like SMN2 C. 859g > C. Array dPCR can be easily used to measure SMN1 and SMN2 copy numbers accurately in DNA samples obtained from SMA patients and healthy, non - SMA controls.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Assay and technical information

Since one of the most common strategies to treat SMA is to exploit the presence of SMN2 gene, High - throughput Screens of various types have been developed to screen for small molecules that increase SMN2 Expression. However, changes in protein expression of endogenous SMN2 genes can sometimes be masked by the presence of even a single copy of SMN1 gene, which complicates assessment of SMN2 expression. One method used to overcome this challenge is to use cells that lack SMN1, such as those derived from SMA patients. Sma patient cells that are cultured in vitro can be used to measure changes in levels of SMN protein and mRNA derived from endogenous SMN2 gene. These techniques have been used effectively to validate new therapeutic approaches and are discussed in greater detail in other sections of this review but are less suited to high - throughput applications. As discussed in previous section, there are also technical considerations when measuring SMN Expression in primary cells, Due to Cell - To - Cell variability of SMN Expression in response to changes in age, cell density, composition of culture medium, passage number, and cell cycle. 78 169 These considerations have made it difficult to use primary cell models to develop Assays that are amenable to High - throughput screening of hundreds of thousands of compounds, Although recent advances are making this more feasible and are discussed in Motor Neuron Assays and High - Content Screens section. To overcome such difficulties, assays have been developed in immortalize cell lines that use surrogates to predict changes in endogenous SMN2 Expression levels. In this section, we discuss reporter assays that have been developed to identify small molecules that can modify SMN2 Expression. One of the first methods explored to identify compounds that can increase SMN protein levels is based on regulation of SMN transcription. Promoters for SMN1 and SMN2 are nearly identical and have been shown to have similar levels of Expression. 170 171 As discussed previously, SMN2 gene primarily produces truncated mRNA isoform that lacks exon 7 and just 10% - 20% of SMN2 mRNA includes exon 7 and encodes for stable full - length SMN protein. Even so, enhancing transcription of SMN2 should increase the overall amount of full - length SMN mRNA, without changing the ratio of exon 7 Splicing in these transcripts. First SMA reporter assay To take advantage of this method, use SMN2 promoter to identify compounds that could increase SMN2 transcription. 84 in this assay, beta - lactamase was used as surrogate for SMN2 Expression. Reporter was clone downstream of 3. 4 kb of SMN2 promoter. Reporter was transfected into NSC - 34 Cell line hybrid of mouse Spinal cord cells and mouse neuroblastoma. 172 Treatment with either trichostatin or sodium butyrate, Two histone deacetylase inhibitors known to increase SMN Expression, 30 173 increase BLA Expression twofold. This assay was used to identify the C5 - substitute 2 4 - diaminoquinazoline series of compounds. 84 these compounds increase full - length SMN mRNA, exon 7 inclusion, and SMN protein levels.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Current testing regimes

Spinal muscular atrophy, autosomal recessive neuromuscular disorder characterized by loss of alpha motor neurons, causes severe muscle weakness and atrophy presenting at or shortly after birth. 1 2 SMA is the leading genetic cause of infant death after cystic fibrosis. 3 incidence of SMA is 1 in 6000 - 10 000 live births, and carrier frequency is 1: 40 - 80 among different ethnic groups. 4 5 6 7 Four clinical types of SMA are classified based on age of onset and severity of disease: 1 very weak infants unable to sit unsupported, weak sitters but unable to stand, ambulant patients with weaker legs than arms, and adult onset SMA. Early detection of SMA can be critical for long - term quality of life due to the availability of two early treatments, nusinersen 8 and Zolgensma, 9 which have received FDA approval for amelioration of SMA symptoms. Disease causing gene, SMN1, and its paralog SMN 2, reside in the ~2 - Mb region on 5q with large number of complicated segmental and inverted segmental duplications. Smn2 is 875 kb away from SMN1 and is created by ancestral gene duplication that is unique to the human lineage. 10 11 genomic regions around SMN1 / 2 are subject to unequal crossing over and gene conversion, resulting in variable copy numbers of SMN1 and SMN2. 7 12 Importantly, SMN2 has > 99. 9% sequence identity to SMN1 and one of base differences, NM_000344. 3: C. 840c > T in exon 7, has critical functional consequence. By interrupting splicing enhancer, C. 840t promotes skipping of exon 7, resulting in the vast majority of SMN2 - derive transcripts being unstable and not fully functional. Approximately 95% of SMA cases result from biallelic absence of functional C. 840c nucleotide 14 caused by either deletion of SMN1 or gene conversion to SMN2. In the remaining 5% of SMA cases, patients also have other pathogenic variants in SMN1. 15 SMN2 can produce small amount of functional protein, and the number of SMN2 copies in an individual modifies disease severity and is highly correlated with clinical types described above. 16 due to high incidence rate and disease severity, population - wide SMA screening is recommended by the American College of Medical Genetics and Genomics. 17 utility of population - wide carrier screening has been demonstrated in pilot studies. 18 keys to screening for SMA are determining the copy number of SMN1 for SMA diagnosis and carrier testing and determining copy number of SMN2 for clinical classification and prognosis. Traditionally, SMA testing and carrier testing are done with polymerase chain reaction base assays, such as quantitative PCR, 19 multiplex ligation - dependent probe amplification, 20 21 and digital PCR. 12 22 These methods primarily determine copy number of SMN1 based on the C. 840c > T site that differs between SMN1 and SMN2. With recent advances in Next - Generation sequencing, it is now possible to profile large numbers of genes or even entire genome at high throughput and in clinically relevant timeframe.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Introduction

Spinal muscular atrophy is caused by a mutation in survival motor neuron 1 gene. This gene is responsible for producing survival motor neuron protein, which maintains health and normal function of motor neurons. In people with spinal muscular atrophy, both copies of SMN1 gene are mutate, leading to decreased production of SMN protein. Without a proper level of SMN protein, motor neurons in the spinal cord will be lose, preventing muscles from receiving proper signals from the brain. 5 every child with spinal muscular atrophy is affected differently, and it is important to note that symptoms can vary greatly according to age of onset and disease severity. Children may experience progressive muscle weakness in muscles closest to the centre of the body, such as shoulders, thighs, and pelvis. These muscles enable activities such as crawling, walking, sitting up, and controlling head movement. Breathing and swallowing may also be affect. 7 all individuals with spinal muscular atrophy have at least one backup gene, known as SMN2. The SMN2 gene has a similar structure to SMN1, but only a small amount of SMN protein it produces is fully functional. This low level of SMN protein is not effective enough to sustain survival of motor neurons in CNS. The 11 - 13 number of SMN2 genes may vary, and higher SMN2 copy number is associated with less - severe symptoms of spinal muscular atrophy. 5 13 14 disease has a wide range of symptoms and, although there is strong correlation between SMN2 copies and disease severity, there are exceptions. Experts therefore recommend that care decisions are made based on the child's functional ability, and not on SMN2 copy number. However, SMN2 copy number is used as key criteria for enrolment in clinical trials.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

SUBJECTS AND METHODS

Evolution of human SMN locus. Human SMN1 and SMN2 genes were derived by duplication of proto - SMN gene after human - chimpanzee split. The yellow bar represents only functional base change that distinguishes SMN2 from SMN1 which is signified by canonical transcript position as C. 840c > T. Copy number of each gene on single chromosome is indicated in bracket and colon formulation. The Canonical SMN chromosomal locus consists of one copy of each gene in centromere - telomere order SMN2 - SMN1. Canonical homozygous genotype represents As /. B. Comparison of SMN1 and SMN2 sequences on either side of gene - defining C. 840c > T base difference. C. Three categories of interlocus homologous recombination between SMN1 and SMN2 generate copy number variants of SMN locus. 1. Recombination and exchange on centromeric side of SMN2 - defining base; 2. Recombination and exchange on centromeric side of SMN2 - defining base; 3. Interlocus gene conversion across SMN2 - defining base region, indicated with double - arrowed line. D. Each recombination event produces two variant SMN chromosome types which are cross - Reference from panel C. Variant chromosomes are ordered by total SMN copy number results for volunteer and Coriell samples. Estimate of scaled proportion of SMN reads that are from SMN1 versus Carrier probability for each subject. Carrier probability can be interpreted as probability that point on x - axis falls to the left of the vertical line at 0. 38. Samples where few SMN reads align to SMN1 are likely SMA carriers, whereas those with a high proportion of SMN1 reads are unlikely SMA carriers. B. 95% Posterior intervals are plotted for each subject. In both and, subjects that do not meet our 10% threshold across our three loci are labelled with stars. Note that their intervals are much wider due to their low coverage. Subjects in both plots are color red if their credible interval is entirely below 0. 38 cutoff and orange if their interval overlaps with 0. 38 Results from MLPA Analysis in 60 subjects. Carrier probability for each sample is stratified by MLPA category. B. Ratio of SMN1 exon 7 to Reference sample versus Carrier probability for each sample. Vertical lines at 0. 7 and 1. 3 represent thresholds for copy number loss and gain, respectively. In both and, tan, black, and Green points represent samples that have less than, equal, and more than two copies of SMN1 exon 7, respectively.


INTRODUCTION

Spinal muscular atrophy is one of the most common autosomal recessive disorders characterized by progressive muscle weakness caused by degeneration of spinal anterior horn cells. Sma has a prevalence of 1 / 6 000 to 1 / 10 000 births and carrier frequency of 1 / 40 to 1 / 50. According to age of onset and severity of symptoms, patients with SMA are subdivided into three clinical types. Type I is the most severe form with onset at birth to first few months and death by 2 years of life. Type II, intermediate form, is characterized by onset before 18 months of age and survival beyond 4 yr - old age. Type III is the mildest form with onset after the age of 2 yr and survival into adulthood. All types of SMA are associated with homozygous deletion in survival motor neuron 1 gene. Smn1 and its homologous gene, SMN2, are located on 5q13. Two SMN genes are different at only five nucleotide exchanges within their 3 ends. In contrast to SMN1, expression of SMN2 protein is truncated by skipping of exon 7 by single nucleotide exchange. Approximately 94% of SMA patients lack both copies of SMN1 exon 7, which can be detected by commonly used molecular analyses. As carrier frequency in the population is high, carrier test for SMA is an important issue in genetic counseling. Until now, several quantitative PCR methods for SMN1 analysis have been developed for carrier detection. However, these methods were intricate and easily submitted to errors. Recently, report quantitative real - time PCR assays allow specific amplification of only SMN1 gene, and have become powerful tools to avoid these problems. However, these tests still include several limitations in relation to specificity, and cost - effectiveness. In consideration of these defects, we developed a reliable quantitative real - time PCR method using SMN1 gene specific primers and SYBR Green I dye for carrier detection of SMA. The Comparative Ct method was used to quantify copy numbers of SMN1 gene. This test allows us to analyze large number of samples efficiently. Here, we report results of quantitative analysis of SMN1 gene in SMA patients and parents, and estimate carrier frequency in the Korean population.


RESULTS

Our major results are summarise in Table 1. In general, studied variants were almost completely absent from chromosomes with single SMN1 copy, but they were frequently detected in those carrying two copies of gene. Carriers. One classical 1 / 0 carrier presented variants whereas 7 of 32 2 / 0 carriers were positive. Interestingly, 3 / 0 carrier was negative for both variants. All individuals with variants were unrelated and shared 20 - repeat allele for marker D 5 S 1556. Further, five of them, who were from the Canary Islands, showed 24 - repeat allele for marker D 5 F 149S1. Non - carriers. All 1 / 1 individuals were negative for studied variants, whereas 11 out of 58 subjects with three SMN1 copies were positive. Four individuals in this last subgroup also had homozygous absence of SMN2 genes, three of whom show variants. The comparison between 2 / 0 carriers vs. 1 / 1 controls was also significant for the presence of variants. Sma patients. None of the variants were found in 16 SMA patients who lacked SMN1. However, four out of 20 SMA patients with SMN2 - SMN1 hybrid genes present c. * 211_ * 212del variant.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

RESULTS

Carrier testing for individuals in the general population, or individuals with family history of SMA, or couples who are planning pregnancy or who are already pregnant. Pediatric or adult diagnostic testing when diagnosis of SMA is suspect. Test 452140, Prenatal Spinal Muscular Atrophy testing, should be used for Prenatal diagnosis for at - risk pregnancies, when both parents are carriers or when severe joint contractures are found on fetal ultrasound. The Copy number of SMN1 exon 7 is assessed relative to internal standard reference genes by quantitative polymerase chain reaction. Mathematical algorithms calculate 0 1 2 or 3 copies with statistical confidence. When no copies of SMN1 are detect, primer and probe binding sites are sequence to rule out variants that could interfere with copy number analysis and SMN2 copy number is assessed by digital droplet PCR analysis relative to internal standard reference gene. Individuals with one copy of SMN1 are predicted to be carriers of SMA; those with two or more copies have reduced carrier risk. For carrier screening, when two copies of SMN1 are detect, allelic discrimination qPCR targeting C. * 3 + 80T > G in SMN1 is perform. Presence or absence of C. * 3 + 80T > G correlates with increased or decreased risk, respectively, of being a silent carrier. The 1 2 copy number of SMN1 exon 7 is assessed relative to internal standard reference genes by quantitative polymerase chain reaction. On. Mathematical algorithms calculate 0 1 2 or 3 copies with statistical confidence. When no copies of SMN1 are detect, primer and probe binding sites are sequence to rule out variants that could interfere with copy number analysis and SMN2 copy number is assessed by digital droplet PCR analysis relative to internal standard reference gene. Individuals with one copy of SMN1 are predicted to be carriers of SMA; those with two or more copies have reduced carrier risk. For carrier screening, when two copies of SMN1 are detect, allelic discrimination qPCR targeting C. * 3 + 80T > G in SMN1 is perform. Presence or absence of C. * 3 + 80T > G correlates with increased or decreased risk, respectively, of being a silent carrier. 1 2 Spinal Muscular Atrophy is an autosomal recessive neurodegenerative disorder with variable age at onset and severity, characterized by progressive degeneration of lower motor neurons in the spinal cord and brain stem, leading to muscle weakness, and in its most common form, respiratory failure by age two. Complications of SMA may include poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint deformities. In severely affected individuals, abnormal fetal ultrasound findings may include congenital joint contractures, polyhydramnios, and decreased fetal movement. 3 Treatment is supportive. Target therapies may be available for some individuals. Approximately 94% of affected individuals have 0 copies of SMN1 gene; in these individuals, increase in number of copies of SMN2 gene correlates with reduced disease severity.


Spinal muscular atrophy

Extra copies of SMN2 gene do not cause spinal muscular atrophy, but they modify the severity of disorder. This condition is characterized by loss of motor neurons that leads to weakness and wasting in muscles used for movement that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among types. All individuals with spinal muscular atrophy have mutations in both copies of the SMN1 gene. As a result, little or no SMN protein is produced from this gene. The SMN2 gene can help replace some of the missing SMN protein. In people with spinal muscular atrophy, having multiple copies of SMN2 gene is usually associated with less severe features of condition that develop later in life. Affected individuals with one or two functional copies of SMN2 gene generally have severe muscle weakness that begins at birth or in infancy. Affected individuals with four or more copies of SMN2 gene typically have mild muscle weakness that may not become noticeable until adulthood. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy. Researchers suggest that shortage of SMN protein leads to inefficient assembly of machinery needed to process pre - mRNA. Lack of mature mRNA and subsequently, proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. Loss of motor neurons leads to signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to reduction in amount of SMN protein. Some research findings indicate that shortage of SMN protein impairs formation and function of axons and dendrites, leading to death of motor neurons. While the mechanism is not clear, it is apparent that increasing SMN2 gene copy number leads to an increase in SMN protein production, which improves function and survival of motor neurons and results in less severe disease.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

logo

Plex.page is an Online Knowledge, where all the summaries are written by a machine. We aim to collect all the knowledge the World Wide Web has to offer.

Partners:
Nvidia inception logo

© All rights reserved
2021 made by Algoritmi Vision Inc.

If you believe that any of the summaries on our website lead to misinformation, don't hesitate to contact us. We will immediately review it and remove the summaries if necessary.

If your domain is listed as one of the sources on any summary, you can consider participating in the "Online Knowledge" program, if you want to proceed, please follow these instructions to apply.
However, if you still want us to remove all links leading to your domain from Plex.page and never use your website as a source, please follow these instructions.