Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease - PubMed (original) (raw)
. 1996 Nov;59(5):1057-65.
Affiliations
- PMID: 8900234
- PMCID: PMC1914839
Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease
E Hahnen et al. Am J Hum Genet. 1996 Nov.
Abstract
Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients, as well as direct sequencing and single-strand conformation analysis of all patients, revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5' end of the SMN genes suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-stimulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the alpha-globin cluster, and the polymerase alpha arrest sites. This may explain why independent hybrid SMN genes show identical sequences.
Similar articles
- Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.
Parsons DW, McAndrew PE, Iannaccone ST, Mendell JR, Burghes AH, Prior TW. Parsons DW, et al. Am J Hum Genet. 1998 Dec;63(6):1712-23. doi: 10.1086/302160. Am J Hum Genet. 1998. PMID: 9837824 Free PMC article. - Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA).
Hahnen E, Schönling J, Rudnik-Schöneborn S, Raschke H, Zerres K, Wirth B. Hahnen E, et al. Hum Mol Genet. 1997 May;6(5):821-5. doi: 10.1093/hmg/6.5.821. Hum Mol Genet. 1997. PMID: 9158159 - Hybrid survival motor neuron genes in Japanese patients with spinal muscular atrophy.
Nishio H, Horikawa H, Yakura H, Sugie K, Nakamuro T, Koterazawa K, Ishikawa Y, Lee MJ, Wada H, Takeshima Y, Matsuo M, Sumino K. Nishio H, et al. Acta Neurol Scand. 1999 Jun;99(6):374-80. doi: 10.1111/j.1600-0404.1999.tb07367.x. Acta Neurol Scand. 1999. PMID: 10577272 - An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).
Wirth B. Wirth B. Hum Mutat. 2000;15(3):228-37. doi: 10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9. Hum Mutat. 2000. PMID: 10679938 Review. - Genetic testing and risk assessment for spinal muscular atrophy (SMA).
Ogino S, Wilson RB. Ogino S, et al. Hum Genet. 2002 Dec;111(6):477-500. doi: 10.1007/s00439-002-0828-x. Epub 2002 Oct 3. Hum Genet. 2002. PMID: 12436240 Review.
Cited by
- Beyond copy number: A new, rapid, and versatile method for sequencing the entire SMN2 gene in SMA patients.
Blasco-Pérez L, Paramonov I, Leno J, Bernal S, Alias L, Fuentes-Prior P, Cuscó I, Tizzano EF. Blasco-Pérez L, et al. Hum Mutat. 2021 Jun;42(6):787-795. doi: 10.1002/humu.24200. Epub 2021 Apr 6. Hum Mutat. 2021. PMID: 33739559 Free PMC article. - Development of a Multiplex Real-Time PCR Assay for the Newborn Screening of SCID, SMA, and XLA.
Gutierrez-Mateo C, Timonen A, Vaahtera K, Jaakkola M, Hougaard DM, Bybjerg-Grauholm J, Baekvad-Hansen M, Adamsen D, Filippov G, Dallaire S, Goldfarb D, Schoener D, Wu R. Gutierrez-Mateo C, et al. Int J Neonatal Screen. 2019 Nov 2;5(4):39. doi: 10.3390/ijns5040039. eCollection 2019 Dec. Int J Neonatal Screen. 2019. PMID: 33072998 Free PMC article. - SMN-inducing compounds for the treatment of spinal muscular atrophy.
Lorson MA, Lorson CL. Lorson MA, et al. Future Med Chem. 2012 Oct;4(16):2067-84. doi: 10.4155/fmc.12.131. Future Med Chem. 2012. PMID: 23157239 Free PMC article. Review. - Update on Biomarkers in Spinal Muscular Atrophy.
Pino MG, Rich KA, Kolb SJ. Pino MG, et al. Biomark Insights. 2021 Aug 14;16:11772719211035643. doi: 10.1177/11772719211035643. eCollection 2021. Biomark Insights. 2021. PMID: 34421296 Free PMC article. Review. - Newborn Screening for Spinal Muscular Atrophy: A 2.5-Year Experience in Hyogo Prefecture, Japan.
Sonehara S, Bo R, Nambu Y, Iketani K, Lee T, Shimomura H, Ueda M, Takeshima Y, Iijima K, Nozu K, Nishio H, Awano H. Sonehara S, et al. Genes (Basel). 2023 Dec 14;14(12):2211. doi: 10.3390/genes14122211. Genes (Basel). 2023. PMID: 38137033 Free PMC article.
References
- Am J Hum Genet. 1990 Jun;46(6):1178-86 - PubMed
- Crit Rev Immunol. 1989;9(3):173-200 - PubMed
- Cell. 1993 Jan 15;72(1):143-51 - PubMed
- Nat Genet. 1992 Dec;2(4):292-300 - PubMed
- Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6801-5 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical