Abstract
Alström syndrome is a clinically complex disorder characterized by childhood retinal degeneration leading to blindness, sensorineural hearing loss, obesity, type 2 diabetes mellitus, cardiomyopathy, systemic fibrosis, and pulmonary, hepatic, and renal failure. Alström syndrome is caused by recessively inherited mutations in the ALMS1 gene, which codes for a putative ciliary protein. Alström syndrome is characterized by extensive allelic heterogeneity, however, founder effects have been observed in some populations. To date, more than 100 causative ALMS1 mutations have been identified, mostly frameshift and non-sense alterations resulting in termination signals in ALMS1. Here, we report a complex Turkish kindred in which sequence analysis uncovered an insertion of a novel 333 basepair Alu Ya5 SINE retrotransposon in the ALMS1 coding sequence, a previously unrecognized mechanism underlying the mutations causing Alström syndrome. It is extraordinarily rare to encounter the insertion of an Alu retrotransposon in the coding sequence of a gene. The high frequency of the mutant ALMS1 allele in this isolated population suggests that this recent retrotransposition event spreads quickly, and may be used as a model to study the population dynamics of deleterious alleles in isolated communities.
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Acknowledgments
The authors are grateful to the individuals with Alström syndrome and their families who continue to show enthusiastic support of research efforts. This work was supported by National Institutes of Health grant HD036878 (JDM, GBC, JKN) and by The Jackson Laboratory institutional multimedia, allele typing, and sequencing services supported by US PHS National Institutes of Health grant CA34196.
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M. Taşkesen, G. B. Collin, and A. V. Evsikov contributed equally to this work.
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Taşkesen, M., Collin, G.B., Evsikov, A.V. et al. Novel Alu retrotransposon insertion leading to Alström syndrome. Hum Genet 131, 407–413 (2012). https://doi.org/10.1007/s00439-011-1083-9
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DOI: https://doi.org/10.1007/s00439-011-1083-9