Novel Alu retrotransposon insertion leading to Alström syndrome

• Published in: Human genetics Vol. 131; no. 3; pp. 407 - 413
• Main Authors: Taşkesen, Mustafa, Collin, Gayle B., Evsikov, Alexei V., Güzel, Ayşegül, Özgül, R. Köksal, Marshall, Jan D., Naggert, Jürgen K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2012; Springer; Springer Nature B.V
• Subjects: Alstrom Syndrome - genetics; Alu Elements - genetics; Analysis; Base pairs; Biomedical and Life Sciences; Biomedicine; Blindness; Cardiomyopathy; Child development; Children; Chromosomes, Human, Pair 13; Consent; Diabetes; Diabetes mellitus; Families & family life; Female; Fibrosis; Founder effect; Gene Function; Hearing loss; Human Genetics; Humans; Insertion; Laboratories; Liver; Lung; Lung diseases; Male; Medical prognosis; Metabolic Diseases; Molecular Medicine; Mutagenesis, Insertional; Mutation; Obesity; Original Investigation; Patient assessment; Pediatrics; Pedigree; Population dynamics; Population genetics; Proteins; Renal failure; retinal degeneration; Retroelements; Retrotransposition; Retrotransposons; Type 2 diabetes; Turkey; Postaxial Polydactyly; Sensorineural Hearing Loss; Truncal Obesity; Digital Anomaly; Cone Dystrophy
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-1083-9

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.