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. 1998 Jul;63(1):37–44. doi: 10.1086/301918

Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family.

L Campbell 1, R J Daniels 1, V Dubowitz 1, K E Davies 1
PMCID: PMC1377239  PMID: 9634516

Abstract

Spinal muscular atrophy (SMA) is a common fatal motor-neuron disorder characterized by degeneration of the anterior horn cells of the spinal cord, which results in proximal muscle weakness. Three forms of the disease, exhibiting differing phenotypic severity, map to chromosome 5q13 in a region of unusually high genomic variability. The SMA-determining gene (SMN) is deleted or rearranged in patients with SMA of all levels of severity. A high de novo mutation rate has been estimated for SMA, based on the deletion of multicopy microsatellite markers. We present a type I SMA family in which a mutant SMA chromosome has undergone a second mutation event. Both the occurrence of three affected siblings harboring this same mutation in one generation of this family and the obligate-carrier status of their mother indicate the existence of maternal germ-line mosaicism for cells carrying the second mutation. The existence of secondary mutational events and of germ-line mosaicism has implications for the counseling of SMA families undergoing prenatal genetic analysis.

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Selected References

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  1. 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. doi: 10.1093/hmg/5.12.1971. [DOI] [PubMed] [Google Scholar]
  2. Brzustowicz L. M., Lehner T., Castilla L. H., Penchaszadeh G. K., Wilhelmsen K. C., Daniels R., Davies K. E., Leppert M., Ziter F., Wood D. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990 Apr 5;344(6266):540–541. doi: 10.1038/344540a0. [DOI] [PubMed] [Google Scholar]
  3. Burlet P., Bürglen L., Clermont O., Lefebvre S., Viollet L., Munnich A., Melki J. Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. J Med Genet. 1996 Apr;33(4):281–283. doi: 10.1136/jmg.33.4.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bussaglia E., Clermont O., Tizzano E., Lefebvre S., Bürglen L., Cruaud C., Urtizberea J. A., Colomer J., Munnich A., Baiget M. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat Genet. 1995 Nov;11(3):335–337. doi: 10.1038/ng1195-335. [DOI] [PubMed] [Google Scholar]
  5. Bürglen L., Seroz T., Miniou P., Lefebvre S., Burlet P., Munnich A., Pequignot E. V., Egly J. M., Melki J. The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease. Am J Hum Genet. 1997 Jan;60(1):72–79. [PMC free article] [PubMed] [Google Scholar]
  6. Campbell L., Potter A., Ignatius J., Dubowitz V., Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet. 1997 Jul;61(1):40–50. doi: 10.1086/513886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Capon F., Lo Cicero S., Levato C., Novelli G., Dallapiccola B. De novo deletions of the 5q13 region and prenatal diagnosis of spinal muscular atrophy. Prenat Diagn. 1995 Jan;15(1):93–94. doi: 10.1002/pd.1970150121. [DOI] [PubMed] [Google Scholar]
  8. Cobben J. M., van der Steege G., Grootscholten P., de Visser M., Scheffer H., Buys C. H. 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] [Google Scholar]
  9. Coovert D. D., Le T. T., McAndrew P. E., Strasswimmer J., Crawford T. O., Mendell J. R., Coulson S. E., Androphy E. J., Prior T. W., Burghes A. H. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997 Aug;6(8):1205–1214. doi: 10.1093/hmg/6.8.1205. [DOI] [PubMed] [Google Scholar]
  10. Daniels R. J., Campbell L., Rodrigues N. R., Francis M. J., Morrison K. E., McLean M., MacKenzie A., Ignatius J., Dubowitz V., Davies K. E. Genomic rearrangements in childhood spinal muscular atrophy: linkage disequilibrium with a null allele. J Med Genet. 1995 Feb;32(2):93–96. doi: 10.1136/jmg.32.2.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daniels R. J., Suthers G. K., Morrison K. E., Thomas N. H., Francis M. J., Mathew C. G., Loughlin S., Heiberg A., Wood D., Dubowitz V. Prenatal prediction of spinal muscular atrophy. J Med Genet. 1992 Mar;29(3):165–170. doi: 10.1136/jmg.29.3.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Devriendt K., Lammens M., Schollen E., Van Hole C., Dom R., Devlieger H., Cassiman J. J., Fryns J. P., Matthijs G. Clinical and molecular genetic features of congenital spinal muscular atrophy. Ann Neurol. 1996 Nov;40(5):731–738. doi: 10.1002/ana.410400509. [DOI] [PubMed] [Google Scholar]
  13. DiDonato C. J., Ingraham S. E., Mendell J. R., Prior T. W., Lenard S., Moxley R. T., 3rd, Florence J., Burghes A. H. Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity? Ann Neurol. 1997 Feb;41(2):230–237. doi: 10.1002/ana.410410214. [DOI] [PubMed] [Google Scholar]
  14. Fischer U., Liu Q., Dreyfuss G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell. 1997 Sep 19;90(6):1023–1029. doi: 10.1016/s0092-8674(00)80368-2. [DOI] [PubMed] [Google Scholar]
  15. Francis M. J., Nesbit M. A., Theodosiou A. M., Rodrigues N. R., Campbell L., Christodoulou Z., Qureshi S. J., Porteous D. J., Brookes A. J., Davies K. E. Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13. Genomics. 1995 May 20;27(2):366–369. doi: 10.1006/geno.1995.1059. [DOI] [PubMed] [Google Scholar]
  16. Gilliam T. C., Brzustowicz L. M., Castilla L. H., Lehner T., Penchaszadeh G. K., Daniels R. J., Byth B. C., Knowles J., Hislop J. E., Shapira Y. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature. 1990 Jun 28;345(6278):823–825. doi: 10.1038/345823a0. [DOI] [PubMed] [Google Scholar]
  17. 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. doi: 10.1093/hmg/4.10.1927. [DOI] [PubMed] [Google Scholar]
  18. 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. doi: 10.1093/hmg/6.5.821. [DOI] [PubMed] [Google Scholar]
  19. Hahnen E., Schönling J., Rudnik-Schöneborn S., Zerres K., Wirth B. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am J Hum Genet. 1996 Nov;59(5):1057–1065. [PMC free article] [PubMed] [Google Scholar]
  20. Humbert S., van Vuuren H., Lutz Y., Hoeijmakers J. H., Egly J. M., Moncollin V. p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair. EMBO J. 1994 May 15;13(10):2393–2398. doi: 10.1002/j.1460-2075.1994.tb06523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Iwahashi H., Eguchi Y., Yasuhara N., Hanafusa T., Matsuzawa Y., Tsujimoto Y. Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy. Nature. 1997 Nov 27;390(6658):413–417. doi: 10.1038/37144. [DOI] [PubMed] [Google Scholar]
  22. Lefebvre S., Burlet P., Liu Q., Bertrandy S., Clermont O., Munnich A., Dreyfuss G., Melki J. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997 Jul;16(3):265–269. doi: 10.1038/ng0797-265. [DOI] [PubMed] [Google Scholar]
  23. Lefebvre S., Bürglen L., Reboullet S., Clermont O., Burlet P., Viollet L., Benichou B., Cruaud C., Millasseau P., Zeviani M. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan 13;80(1):155–165. doi: 10.1016/0092-8674(95)90460-3. [DOI] [PubMed] [Google Scholar]
  24. Liu Q., Fischer U., Wang F., Dreyfuss G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell. 1997 Sep 19;90(6):1013–1021. doi: 10.1016/s0092-8674(00)80367-0. [DOI] [PubMed] [Google Scholar]
  25. Matthijs G., Schollen E., Legius E., Devriendt K., Goemans N., Kayserili H., Apäk M. Y., Cassiman J. J. Unusual molecular findings in autosomal recessive spinal muscular atrophy. J Med Genet. 1996 Jun;33(6):469–474. doi: 10.1136/jmg.33.6.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McAndrew P. E., Parsons D. W., Simard L. R., Rochette C., Ray P. N., Mendell J. R., Prior T. W., Burghes A. H. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet. 1997 Jun;60(6):1411–1422. doi: 10.1086/515465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McNaughton J. C., Broom J. E., Hill D. F., Jones W. A., Marshall C. J., Renwick N. M., Stockwell P. A., Petersen G. B. A cluster of transposon-like repetitive sequences in intron 7 of the human dystrophin gene. J Mol Biol. 1993 Jul 5;232(1):314–321. doi: 10.1006/jmbi.1993.1389. [DOI] [PubMed] [Google Scholar]
  28. Melki J., Abdelhak S., Sheth P., Bachelot M. F., Burlet P., Marcadet A., Aicardi J., Barois A., Carriere J. P., Fardeau M. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature. 1990 Apr 19;344(6268):767–768. doi: 10.1038/344767a0. [DOI] [PubMed] [Google Scholar]
  29. Melki J., Lefebvre S., Burglen L., Burlet P., Clermont O., Millasseau P., Reboullet S., Bénichou B., Zeviani M., Le Paslier D. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474–1477. doi: 10.1126/science.7910982. [DOI] [PubMed] [Google Scholar]
  30. Melki J., Sheth P., Abdelhak S., Burlet P., Bachelot M. F., Lathrop M. G., Frezal J., Munnich A. Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators. Lancet. 1990 Aug 4;336(8710):271–273. doi: 10.1016/0140-6736(90)91803-i. [DOI] [PubMed] [Google Scholar]
  31. Morrison K. E., Daniels R. J., Suthers G. K., Flynn G. A., Francis M. J., Buckle V. J., Davies K. E. High-resolution genetic map around the spinal muscular atrophy (SMA) locus on chromosome 5. Am J Hum Genet. 1992 Mar;50(3):520–527. [PMC free article] [PubMed] [Google Scholar]
  32. Munsat T. L., Davies K. E. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(5-6):423–428. doi: 10.1016/s0960-8966(06)80015-5. [DOI] [PubMed] [Google Scholar]
  33. Parano E., Pavone L., Falsaperla R., Trifiletti R., Wang C. Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy. Ann Neurol. 1996 Aug;40(2):247–251. doi: 10.1002/ana.410400219. [DOI] [PubMed] [Google Scholar]
  34. Parsons D. W., McAndrew P. E., Monani U. R., Mendell J. R., Burghes A. H., Prior T. W. 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. doi: 10.1093/hmg/5.11.1727. [DOI] [PubMed] [Google Scholar]
  35. Pizzuti A., Pieretti M., Fenwick R. G., Gibbs R. A., Caskey C. T. A transposon-like element in the deletion-prone region of the dystrophin gene. Genomics. 1992 Jul;13(3):594–600. doi: 10.1016/0888-7543(92)90129-g. [DOI] [PubMed] [Google Scholar]
  36. Rodrigues N. R., Owen N., Talbot K., Ignatius J., Dubowitz V., Davies K. E. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum Mol Genet. 1995 Apr;4(4):631–634. doi: 10.1093/hmg/4.4.631. [DOI] [PubMed] [Google Scholar]
  37. Rodrigues N. R., Owen N., Talbot K., Patel S., Muntoni F., Ignatius J., Dubowitz V., Davies K. E. Gene deletions in spinal muscular atrophy. J Med Genet. 1996 Feb;33(2):93–96. doi: 10.1136/jmg.33.2.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Roy N., Mahadevan M. S., McLean M., Shutler G., Yaraghi Z., Farahani R., Baird S., Besner-Johnston A., Lefebvre C., Kang X. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995 Jan 13;80(1):167–178. doi: 10.1016/0092-8674(95)90461-1. [DOI] [PubMed] [Google Scholar]
  39. Sargent C. A., Chalmers I. J., Leversha M., Affara N. A. A rearrangement on chromosome 5 of an expressed human beta-glucuronidase pseudogene. Mamm Genome. 1994 Dec;5(12):791–796. doi: 10.1007/BF00292015. [DOI] [PubMed] [Google Scholar]
  40. Selig S., Bruno S., Scharf J. M., Wang C. H., Vitale E., Gilliam T. C., Kunkel L. M. Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3702–3706. doi: 10.1073/pnas.92.9.3702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Simard L. R., Rochette C., Semionov A., Morgan K., Vanasse M. SMN(T) and NAIP mutations in Canadian families with spinal muscular atrophy (SMA): genotype/phenotype correlations with disease severity. Am J Med Genet. 1997 Oct 3;72(1):51–58. doi: 10.1002/(sici)1096-8628(19971003)72:1<51::aid-ajmg11>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  42. Talbot K., Ponting C. P., Theodosiou A. M., Rodrigues N. R., Surtees R., Mountford R., Davies K. E. 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. doi: 10.1093/hmg/6.3.497. [DOI] [PubMed] [Google Scholar]
  43. Talbot K., Rodrigues N. R., Ignatius J., Muntoni F., Davies K. E. Gene conversion at the SMN locus in autosomal recessive spinal muscular atrophy does not predict a mild phenotype. Neuromuscul Disord. 1997 May;7(3):198–201. doi: 10.1016/s0960-8966(97)00450-1. [DOI] [PubMed] [Google Scholar]
  44. Theodosiou A. M., Morrison K. E., Nesbit A. M., Daniels R. J., Campbell L., Francis M. J., Christodoulou Z., Davies K. E. Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13. Am J Hum Genet. 1994 Dec;55(6):1209–1217. [PMC free article] [PubMed] [Google Scholar]
  45. 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. doi: 10.1093/hmg/5.2.257. [DOI] [PubMed] [Google Scholar]
  46. Wirth B., Hahnen E., Morgan K., DiDonato C. J., Dadze A., Rudnik-Schöneborn S., Simard L. R., Zerres K., Burghes A. H. 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. doi: 10.1093/hmg/4.8.1273. [DOI] [PubMed] [Google Scholar]
  47. Wirth B., Schmidt T., Hahnen E., Rudnik-Schöneborn S., Krawczak M., Müller-Myhsok B., Schönling J., Zerres K. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling. Am J Hum Genet. 1997 Nov;61(5):1102–1111. doi: 10.1086/301608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. van der Steege G., Draaijers T. G., Grootscholten P. M., Osinga J., Anzevino R., Velonà I., Den Dunnen J. T., Scheffer H., Brahe C., van Ommen G. J. A provisional transcript map of the spinal muscular atrophy (SMA) critical region. Eur J Hum Genet. 1995;3(2):87–95. doi: 10.1159/000472281. [DOI] [PubMed] [Google Scholar]
  49. van der Steege G., Grootscholten P. M., Cobben J. M., Zappata S., Scheffer H., den Dunnen J. T., van Ommen G. J., Brahe C., Buys C. H. 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] [Google Scholar]
  50. van der Steege G., Grootscholten P. M., van der Vlies P., Draaijers T. G., Osinga J., Cobben J. M., Scheffer H., Buys C. H. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet. 1995 Apr 15;345(8955):985–986. [PubMed] [Google Scholar]

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