RESUMO
BACKGROUND: Syndromic hearing loss that results from contiguous gene deletions is uncommon. Deafness-infertility syndrome (DIS) is caused by large contiguous gene deletions at 15q15.3. METHODS: Three families with a novel syndrome characterised by deafness and infertility are described. These three families do not share a common ancestor and do not share identical deletions. Linkage was established by completing a genome-wide scan and candidate genes in the linked region were screened by direct sequencing. RESULTS: The deleted region is about 100 kb long and involves four genes (KIAA0377, CKMT1B, STRC and CATSPER2), each of which has a telomeric duplicate. This genomic architecture underlies the mechanism by which these deletions occur. CATSPER2 and STRC are expressed in the sperm and inner ear, respectively, consistent with the phenotype in persons homozygous for this deletion. A deletion of this region has been reported in one other family segregating male infertility and sensorineural deafness, although congenital dyserythropoietic anaemia type I (CDAI) was also present, presumably due to a second deletion in another genomic region. CONCLUSION: We have identified three families segregating an autosomal recessive contiguous gene deletion syndrome characterised by deafness and sperm dysmotility. This new syndrome is caused by the deletion of contiguous genes at 15q15.3.
Assuntos
Cromossomos Humanos Par 15/genética , Deleção de Genes , Perda Auditiva Neurossensorial/genética , Infertilidade Masculina/genética , Sequências Repetitivas de Ácido Nucleico , Sequências de Repetição em Tandem , Sequência de Bases , Canais de Cálcio , Quebra Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 15/ultraestrutura , Consanguinidade , Creatina Quinase/deficiência , Creatina Quinase/genética , Genes Recessivos , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Canais Iônicos/deficiência , Canais Iônicos/genética , Canais Iônicos/fisiologia , Irã (Geográfico) , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Linhagem , Fosfotransferases (Aceptor do Grupo Fosfato) , Proteínas Tirosina Fosfatases/genética , Pseudogenes , Proteínas de Plasma Seminal , Alinhamento de Sequência , Motilidade dos Espermatozoides/genética , SíndromeRESUMO
BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. METHODS: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. RESULTS AND DISCUSSION: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.
Assuntos
Anormalidades Múltiplas/genética , Proteínas Contráteis/genética , Cifose/genética , Proteínas dos Microfilamentos/genética , Mutação , Coluna Vertebral/anormalidades , DNA/genética , DNA/isolamento & purificação , Feminino , Filaminas , Falanges dos Dedos da Mão/anormalidades , Humanos , Masculino , Metacarpo/anormalidades , FenótipoRESUMO
Syndromic hearing loss that results from contiguous gene deletions is uncommon.Three families with a novel syndrome characterised by deafness and infertility are described. Linkage was established by completing a genome-wide scan and candidate genes in the linked region were screened by direct sequencing. The deleted region is about 100 kb long and involves four genes (KIAA0377, CKMT1B, STRC and CATSPER2), each of which has a telomeric duplicate. This genomic architecture underlies the mechanism by which these deletions occur. CATSPER2 and STRC are expressed in the sperm and inner ear, respectively, consistent with the phenotype in persons homozygous for this deletion. A deletion of this region has been reported in one other family segregating male infertility and sensorineural deafness. We have identified three families segregating an autosomal recessive contiguous gene deletion syndrome characterised by deafness and sperm dysmotility. This new syndrome is caused by the deletion of contiguous genes at 15q15.3.