Logo of ajhgLink to Publisher's site
Am J Hum Genet. 1997 Jun; 60(6): 1411–1422.
PMCID: PMC1716150

Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number.


The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Brahe C, Clermont O, Zappata S, Tiziano F, Melki J, Neri G. Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I. Hum Mol Genet. 1996 Dec;5(12):1971–1976. [PubMed]
  • Brahe C, Velonà I, van der Steege G, Zappata S, van de Veen AY, Osinga J, Tops CM, Fodde R, Khan PM, Buys CH, et al. Mapping of two new markers within the smallest interval harboring the spinal muscular atrophy locus by family and radiation hybrid analysis. Hum Genet. 1994 May;93(5):494–501. [PubMed]
  • Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990 Apr 5;344(6266):540–541. [PubMed]
  • Burghes AH, Ingraham SE, Kóte-Jarai Z, Rosenfeld S, Herta N, Nadkarni N, DiDonato CJ, Carpten J, Hurko O, Florence J, et al. Linkage mapping of the spinal muscular atrophy gene. Hum Genet. 1994 Mar;93(3):305–312. [PubMed]
  • Burghes AH, Ingraham SE, McLean M, Thompson TG, McPherson JD, Kote-Jarai Z, Carpten JD, DiDonato CJ, Ikeda JE, Surh L, et al. A multicopy dinucleotide marker that maps close to the spinal muscular atrophy gene. Genomics. 1994 May 15;21(2):394–402. [PubMed]
  • Bürglen L, Lefebvre S, Clermont O, Burlet P, Viollet L, Cruaud C, Munnich A, Melki J. Structure and organization of the human survival motor neurone (SMN) gene. Genomics. 1996 Mar 15;32(3):479–482. [PubMed]
  • Bussaglia E, Clermont O, Tizzano E, Lefebvre S, Bürglen L, Cruaud C, Urtizberea JA, Colomer J, Munnich A, Baiget M, et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat Genet. 1995 Nov;11(3):335–337. [PubMed]
  • Carpten JD, DiDonato CJ, Ingraham SE, Wagner-McPherson C, Nieuwenhuijsen BW, Wasmuth JJ, Burghes AH. A YAC contig of the region containing the spinal muscular atrophy gene (SMA): identification of an unstable region. Genomics. 1994 Nov 15;24(2):351–356. [PubMed]
  • Celi FS, Cohen MM, Antonarakis SE, Wertheimer E, Roth J, Shuldiner AR. Determination of gene dosage by a quantitative adaptation of the polymerase chain reaction (gd-PCR): rapid detection of deletions and duplications of gene sequences. Genomics. 1994 May 15;21(2):304–310. [PubMed]
  • Celi FS, Zenilman ME, Shuldiner AR. A rapid and versatile method to synthesize internal standards for competitive PCR. Nucleic Acids Res. 1993 Feb 25;21(4):1047–1047. [PMC free article] [PubMed]
  • Cobben JM, van der Steege G, Grootscholten P, de Visser M, Scheffer H, Buys CH. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet. 1995 Oct;57(4):805–808. [PMC free article] [PubMed]
  • DiDonato CJ, Chen XN, Noya D, Korenberg JR, Nadeau JH, Simard LR. Cloning, characterization, and copy number of the murine survival motor neuron gene: homolog of the spinal muscular atrophy-determining gene. Genome Res. 1997 Apr;7(4):339–352. [PubMed]
  • DiDonato CJ, Ingraham SE, Mendell JR, Prior TW, Lenard S, Moxley RT, 3rd, Florence J, Burghes AH. Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity? Ann Neurol. 1997 Feb;41(2):230–237. [PubMed]
  • DiDonato CJ, Morgan K, Carpten JD, Fuerst P, Ingraham SE, Prescott G, McPherson JD, Wirth B, Zerres K, Hurko O, et al. Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy. Am J Hum Genet. 1994 Dec;55(6):1218–1229. [PMC free article] [PubMed]
  • Francis MJ, Morrison KE, Campbell L, Grewal PK, Christodoulou Z, Daniels RJ, Monaco AP, Frischauf AM, McPherson J, Wasmuth J, et al. A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13. Hum Mol Genet. 1993 Aug;2(8):1161–1167. [PubMed]
  • Hahnen E, Forkert R, Marke C, Rudnik-Schöneborn S, Schönling J, Zerres K, Wirth B. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum Mol Genet. 1995 Oct;4(10):1927–1933. [PubMed]
  • Hahnen E, Schönling J, Rudnik-Schöneborn S, Raschke H, Zerres K, Wirth B. Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). Hum Mol Genet. 1997 May;6(5):821–825. [PubMed]
  • Kleyn PW, Wang CH, Lien LL, Vitale E, Pan J, Ross BM, Grunn A, Palmer DA, Warburton D, Brzustowicz LM, et al. Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6801–6805. [PMC free article] [PubMed]
  • Laskey RA, Mills AD. Quantitative film detection of 3H and 14C in polyacrylamide gels by fluorography. Eur J Biochem. 1975 Aug 15;56(2):335–341. [PubMed]
  • Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan 13;80(1):155–165. [PubMed]
  • Matthijs G, Schollen E, Legius E, Devriendt K, Goemans N, Kayserili H, Apäk MY, Cassiman JJ. Unusual molecular findings in autosomal recessive spinal muscular atrophy. J Med Genet. 1996 Jun;33(6):469–474. [PMC free article] [PubMed]
  • Melki J, Abdelhak S, Sheth P, Bachelot MF, Burlet P, Marcadet A, Aicardi J, Barois A, Carriere JP, Fardeau M, et al. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature. 1990 Apr 19;344(6268):767–768. [PubMed]
  • Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, Reboullet S, Bénichou B, Zeviani M, Le Paslier D, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474–1477. [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Müller B, Melki J, Burlet P, Clerget-Darpoux F. Proximal spinal muscular atrophy (SMA) types II and III in the same sibship are not caused by different alleles at the SMA locus on 5q. Am J Hum Genet. 1992 May;50(5):892–895. [PMC free article] [PubMed]
  • Parsons DW, McAndrew PE, Monani UR, Mendell JR, Burghes AH, Prior TW. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum Mol Genet. 1996 Nov;5(11):1727–1732. [PubMed]
  • Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919–922. [PubMed]
  • Rodrigues NR, Owen N, Talbot K, Ignatius J, Dubowitz V, Davies KE. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum Mol Genet. 1995 Apr;4(4):631–634. [PubMed]
  • Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995 Jan 13;80(1):167–178. [PubMed]
  • Schwartz M, Sørensen N, Hansen FJ, Hertz JM, Nørby S, Tranebjaerg L, Skovby F. Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy. Hum Mol Genet. 1997 Jan;6(1):99–104. [PubMed]
  • Sestini R, Orlando C, Zentilin L, Gelmini S, Pinzani P, Bianchi S, Selli C, Giacca M, Pazzagli M. Measuring c-erbB-2 oncogene amplification in fresh and paraffin-embedded tumors by competitive polymerase chain reaction. Clin Chem. 1994 Apr;40(4):630–636. [PubMed]
  • Sestini R, Orlando C, Zentilin L, Lami D, Gelmini S, Pinzani P, Giacca M, Pazzagli M. Gene amplification for c-erbB-2, c-myc, epidermal growth factor receptor, int-2, and N-myc measured by quantitative PCR with a multiple competitor template. Clin Chem. 1995 Jun;41(6 Pt 1):826–832. [PubMed]
  • Simard LR, Vanasse M, Rochette C, Morgan K, Lemieux B, Melançon SB, Labuda D. Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): confirmation of close linkage to D5S39 in French Canadian families. Genomics. 1992 Sep;14(1):188–190. [PubMed]
  • Talbot K, Ponting CP, Theodosiou AM, Rodrigues NR, Surtees R, Mountford R, Davies KE. Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? Hum Mol Genet. 1997 Mar;6(3):497–500. [PubMed]
  • Thompson TG, DiDonato CJ, Simard LR, Ingraham SE, Burghes AH, Crawford TO, Rochette C, Mendell JR, Wasmuth JJ. A novel cDNA detects homozygous microdeletions in greater than 50% of type I spinal muscular atrophy patients. Nat Genet. 1995 Jan;9(1):56–62. [PubMed]
  • van der Steege G, Grootscholten PM, Cobben JM, Zappata S, Scheffer H, den Dunnen JT, van Ommen GJ, Brahe C, Buys CH. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am J Hum Genet. 1996 Oct;59(4):834–838. [PMC free article] [PubMed]
  • van der Steege G, Grootscholten PM, van der Vlies P, Draaijers TG, Osinga J, Cobben JM, Scheffer H, Buys CH. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet. 1995 Apr 15;345(8955):985–986. [PubMed]
  • Velasco E, Valero C, Valero A, Moreno F, Hernández-Chico C. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype. Hum Mol Genet. 1996 Feb;5(2):257–263. [PubMed]
  • Viollet L, Bertrandy S, Bueno Brunialti AL, Lefebvre S, Burlet P, Clermont O, Cruaud C, Guénet JL, Munnich A, Melki J. cDNA isolation, expression, and chromosomal localization of the mouse survival motor neuron gene (Smn). Genomics. 1997 Feb 15;40(1):185–188. [PubMed]
  • Wang CH, Xu J, Carter TA, Ross BM, Dominski MK, Bellcross CA, Penchaszadeh GK, Munsat TL, Gilliam TC. Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. Hum Mol Genet. 1996 Mar;5(3):359–365. [PubMed]
  • Wirth B, el-Agwany A, Baasner A, Burghes A, Koch A, Dadze A, Piechaczeck-Wappenschmidt B, Rudnik-Schöneborn S, Zerres K, Schönling J. Mapping of the spinal muscular atrophy (SMA) gene to a 750-kb interval flanked by two new microsatellites. Eur J Hum Genet. 1995;3(1):56–60. [PubMed]
  • Wirth B, Hahnen E, Morgan K, DiDonato CJ, Dadze A, Rudnik-Schöneborn S, Simard LR, Zerres K, Burghes AH. Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. Hum Mol Genet. 1995 Aug;4(8):1273–1284. [PubMed]
  • Wirth B, Pick E, Leutner A, Dadze A, Voosen B, Knapp M, Piechaczek-Wappenschmidt B, Rudnik-Schöneborn S, Schönling J, Cox S, et al. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3. Genomics. 1994 Mar 1;20(1):84–93. [PubMed]
  • Zielenski J, Bozon D, Kerem B, Markiewicz D, Durie P, Rommens JM, Tsui LC. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229–235. [PubMed]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • MedGen
    Related information in MedGen
  • OMIM
    Genome Survey Sequence (GSS) nucleotide records reported in the current articles.
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...