RESUMO
Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.
Assuntos
Caderinas/genética , Perda Auditiva Neurossensorial/genética , Família Multigênica/genética , Mutação/genética , Processamento Alternativo/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas Relacionadas a Caderinas , Caderinas/química , Caderinas/metabolismo , Clonagem Molecular , Sequência Consenso/genética , Cuba , Análise Mutacional de DNA , Éxons/genética , Feminino , Genótipo , Alemanha , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SíndromeRESUMO
ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 modules) proteins constitute a family of zinc metalloproteinases which target and process extracellular matrix proteins. We cloned and characterized a novel human ADAMTS gene, ADAMTS14, which is located on human chromosome 10q2. ADAMTS14 exhibits the characteristic multidomain structure of ADAMTS proteins including four thrombospondin modules and shows highest similarity to ADAMTS3 and ADAMTS2. By RT-PCR analysis we demonstrated that ADAMTS14 is expressed in human retina and also at low levels in adult brain, lung and placenta.
Assuntos
Metaloendopeptidases/genética , Proteínas ADAM , Proteínas ADAMTS , Proteína ADAMTS4 , Sequência de Aminoácidos , Cromossomos Humanos Par 10 , Clonagem Molecular , DNA Complementar/biossíntese , DNA Complementar/química , Desintegrinas/química , Endopeptidases/química , Humanos , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Dados de Sequência Molecular , Pró-Colágeno N-Endopeptidase/química , Retina/metabolismo , Trombospondinas/químicaRESUMO
Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.
Assuntos
Oxigenases de Função Mista/genética , Deficiência de Vitamina K/etiologia , Fatores de Coagulação Sanguínea/metabolismo , Carbono-Carbono Ligases/genética , Saúde da Família , Feminino , Genes Recessivos , Hemorragia/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Oxigenases de Função Mista/efeitos adversos , Linhagem , Fenótipo , Análise de Sequência , Vitamina K/farmacocinética , Deficiência de Vitamina K/congênito , Deficiência de Vitamina K/genética , Vitamina K Epóxido RedutasesRESUMO
Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated and the APCA locus was found to be linked to the short arm of chromosome 19 in two large kindreds. The microsatellite marker UT705 was found to be linked to the APCA locus with two point analysis yielding a maximum lod score of 8.20 at theta max = 0.000 in a five generation pedigree. Linkage to this region was confirmed in a second kindred. The absence of known candidate genes in the region may necessitate a positional cloning approach in order to identify the gene for this disorder.
