A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 83; no. 12; pp. 1025 - 1032
• Main Authors: KALAY, E, DE BROUWER, A. P. M, BRUNNER, H. G, KREMER, H, CAYLAN, R, NABUURS, S. B, WOLLNIK, B, KARAGUZEL, A, HEISTER, J. G. A. M, ERDOL, H, CREMERS, F. P. M, CREMERS, C. W. R. J
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.12.2005; Springer Nature B.V
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Audiometry, Pure-Tone; Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 17; Consanguinity; DNA Mutational Analysis; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Exons; Female; General aspects; Genes, Recessive; Genetic Linkage; Genetic Markers; Haplotypes; Hearing Loss, Sensorineural - genetics; Homozygote; Humans; Hydrogen Bonding; Lod Score; Male; Medical sciences; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Non tumoral diseases; Otorhinolaryngology. Stomatology; Pedigree; Polymorphism, Genetic; Protein Structure, Tertiary; Tandem Repeat Sequences; Turkey - epidemiology; Usher Syndromes - genetics; Turkey; Binding; Deafness; Retinopathy; PDZ; Auditory disorder; Genetic disease; Hearing loss; Macular degeneration; Medicine; Eye disease; USH1G; SANS; Usher syndrome; Cause; Retinal degeneration; ENT disease; Genetics; Atypical; Mutation; Atypical Usher syndrome
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-005-0719-4

Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1-25.3 flanked by the polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at theta=0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the -3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.