Abstract
Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e−16, P=4.264e−10, P=2.722e−8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e−16), SERF1A (P<2e−16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Pearn, J. Incidence, prevalence and gene frequency studies of chronic childhood spinal muscular atrophy. J. Med. Genet. 15, 409–413 (1978).
Cusin, V., Clermont, O., Gerard, B., Chantereau, D. & Elion, J. Prevalence of SMN1 deletion and duplication in carrier and normal populations: implication for genetic counselling. J. Med. Genet. 40, e39 (2003).
Lefebvre, S., Bürglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
Wirth, B., Herz, M., Wetter, A., Moskau, S., Hahnen, E., Rudnik-Schöneborn, S. et al. Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am. J. Hum. Genet. 64, 1340–1356 (1999).
Munsat, T. L. & Davies, K. E. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul. Disord. 2, 423–428 (1992).
Wang, C. H., Finkel, R. S., Bertini, E. S., Schroth, M., Simonds, A., Wong, B. et al. Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J. Child. Neurol. 22, 1027–1049 (2007).
Wirth, B., Garbes, L. & Riessland, M. How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches. Curr. Opin. Genet. Dev. 23, 330–338 (2013).
Rochette, C. F., Gilbert, N. & Simard, L. R. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum. Genet. 108, 255–266 (2001).
Schmutz, J., Martin, J., Terry, A., Couronne, O., Grimwood, J., Lowry, S. et al. The DNA sequence and comparative analysis of human chromosome 5. Nature 431, 268–274 (2004).
Bailey, J. A. & Eichler, E. E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nat. Rev. Genet. 7, 552–564 (2006).
Girirajan, S., Campbell, C. D. & Eichler, E. E. Human copy number variation and complex genetic disease. Annu. Rev. Genet. 45, 203–226 (2011).
Burghes, A. H. When is a deletion not a deletion? When it is converted. Am. J. Hum. Genet. 61, 9–15 (1997).
Monani, U. R., Lorson, C. L., Parsons, D. W., Prior, T. W., Androphy, E. J., Burghes, A. H. et al. A single nucleotide difference that alters splicing patterns distinguishing the SMA gene and SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8, 1177–1183 (1999).
Feldkötter, M., Schwarzer, V., Wirth, R., Wienker, T. F. & Wirth, B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am. J. Hum. Genet. 70, 358–368 (2002).
Wirth, B., Brichta, L., Schrank, B., Lochmüller, H., Blick, S., Baasner, A. et al. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum. Genet 119, 422–428 (2006).
Lamar, K. M. & McNally, E. M. Genetic Modifiers for Neuromuscular Diseases. J. Neuromuscul. Dis. 1, 3–13 (2014).
van Ham, T. J., Holmberg, M. A., van der Goot, A. T., Teuling, E., Garcia-Arencibia, M., Kim, H. E. et al. Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity. Cell 142, 601–612 (2010).
Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G. et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379, 349–353 (1996).
Roy, N., Mahadevan, M. S., McLean, M., Shutler, G., Yaraghi, Z., Farahani, R. et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80, 167–178 (1995).
Burlet, P., Bürglen, L., Clermont, O., Lefebvre, S., Viollet, L., Munnich, A. et al. Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease. J. Med. Genet. 33, 281–283 (1996).
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. 5, 257–263 (1996).
Scharf, J. M., Endrizzi, M. G., Wetter, A., Huang, S., Thompson, T. G., Zerres, K. et al. Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics. Nat. Genet. 20, 83–86 (1998).
Arkblad, E., Tulinius, M., Kroksmark, A. K., Henricsson, M. & Darin, N. A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy. Acta. Paediatr. 98, 865–872 (2009).
Amara, A., Adala, L., Ben Charfeddine, I., Mamaï, O., Mili, A., Lazreg, T. B. et al. Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. Eur. J. Paediatr. Neurol. 16, 167–174 (2012).
He, J., Zhang, Q. J., Lin, Q. F., Chen, Y. F., Lin, X. Z., Lin, M. T. et al. Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy. Gene. 518, 325–329 (2013).
Munsat, T. L. International SMA collaboration. Neuromuscul. Disord. 1, 81 (1991).
R Core Team R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, Austria, 2014).
Brahe, C. Copies of the survival motor neuron gene in spinal muscular atrophy: The more, the better. Neuromuscul. Disord. 10, 274–275 (2000).
Hauke, J., Riessland, M., Lunke, S., Eyüpoglu, I. Y., Blümcke, I., El-Osta, A. et al. Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition. Hum. Mol. Genet. 18, 304–317 (2009).
Hua, Y., Sahashi, K., Hung, G., Rigo, F., Passini, M. A., Bennett, C. F. et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes. Dev. 24, 1634–1644 (2010).
Hua, Y., Sahashi, K., Rigo, F., Hung, G., Horev, G., Bennett, C. F. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123–126 (2011).
Wirth, B., Schmidt, T., Hahnen, E., Rudnik-Schöneborn, S., Krawczak, M., Müller-Myhsok, B. et al. 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. 61, 1102–1111 (1997).
Ogino, S. & Wilson, R. B. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum. Genet. 111, 477–500 (2002).
Campbell, L., Daniels, R. J., Dubowitz, V. & Davies, K. E. Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family. Am. J. Hum. Genet. 63, 37–44 (1998).
Ben-Shachar, S., Orr-Urtreger, A., Bardugo, E., Shomrat, R. & Yaron, Y. Large-scale population screening for spinal muscular atrophy: clinical implications. Genet. Med. 13, 110–114 (2011).
Acknowledgements
This study was supported by a grant no. 173016 from the Ministry of Education, Science and Technological Development, Republic of Serbia.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Rights and permissions
About this article
Cite this article
Brkušanin, M., Kosać, A., Jovanović, V. et al. Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients. J Hum Genet 60, 723–728 (2015). https://doi.org/10.1038/jhg.2015.104
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2015.104
