Hereditary non-syndromic profound deafness affects about 1 in 2000 children prior to language acquisition. In 80% of the cases, the mode of transmission is autosomal recessive. The number of genes involved in these recessive forms of isolated deafness (DFNB genes) has been estimated to between 30 and 100. So far, ten DFNB genes have been mapped to human chromosomes, one of which has been isolated2. By linkage analysis of a single family whose members were affected with profound deafness, some of them presenting with vestibular dysfunction, DFNB2 has been mapped to chromosome 11q13 (ref. 3). The gene responsible for a form of Usher syndrome type I, USH1B, has been assigned to the same chromosomal region4. Usher syndrome associates profound congenital deafness and vestibular dysfunction with retinitis pigmentosa. In the homologous murine region are located the shaker-1 mutations responsible for deafness and vestibular dysfunction. It has been demonstrated that the murine shaker-1 and human USH1B phenotypes result from mutations in the gene encoding myosin-VIIA5,6. Based on mapping data as well as on the similarities between the phenotypes of DFNB2-affected patients and shaker-1 mouse mutants, we have proposed that a defective myosin-VIIA may also be responsible for DFNB2 (ref. 1). Sequence analysis of each of the coding exons of the myosin-VIIA gene (MYO7A) was thus undertaken in the DFNB2-affected family. In the last nucleotide of exon 15, a G to A transition was detected, a type of mutation that is known to decrease the efficiency of splicing7‐14. Accordingly, this result shows that different mutations in MYO7A result in either an isolated or a syndromic form of deafness.

The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene.

From the 'Hemostasis and Thrombosis Research Center, University Hospital, Leiden, The Netherlands; 2Dipartimento Biochimica e Biologia Moleculare, Università degli studi di Ferrara, Ferrara, Italy; diagnostic Haematology, The Royal Melbourne Hospital, Victoria, Australia; 4INSERM CJF 91-01, UFR des Sciences Pharma­ ceutiques et Biologiques, Paris, France; department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; department of Haematology, Charing Cross & Westminster Medical School, London, UK; 7Abteilung Humangenetik, Medizinische Hochschule, Hannover, Germany; 8Section for Hemostasis and Thrombosis, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; ’Department of Biochemistry, School of Medicine, University of Vermont, Burlington, VT, USA; 10First Department of Internal Medicine, Nagoya University School of Mediciné, Tsurumai-cho, Nagoya, Japan; "Cancer Research Institute, Hospital Duran I Reynals, Barcelona, Spain; ,2Biochemisches Labor, Universitats-Kinderklinik Freiburg, Freiburg, Germany; ,3Charter Molecular Genetics Laboratory, Thrombosis Research Institute, London, UK

Protein C deficiency : a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization committee of the ISTH

Identification of 15 Different Candidate Causal Point Mutations and Three Polymorphisms in 19 Patients With Protein S Deficiency Using a Scanning Method for the Analysis of the Protein S Active Gene

Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Although the most common form of the disease is the classical infantile form (Krabbe disease), later-onset forms also have been described. We have analyzed the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD and in 1 patient with classical Krabbe disease. Half of the patients were heterozygous for the large gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that result in deficient galactocerebrosidase activity were also identified in these patients. They include the missense mutations R63H, G95S, M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-nt insertion in the RNA, caused by the aberrant splicing of intron 6. All of these genetic defects are clustered in the first 10 exons of the galactocerebrosidase gene and therefore affect the 50-kD subunit of the mature enzyme. Studies on the distribution and enzymatic activity of the polymorphic alleles 1637T/C (I546/T546) provided support for previous data that had indicated the existence of two galactocerebrosidase forms with different catalytic activities in the general population. Our data also indicate that the mutations occur preferentially in the "low activity" 1637C allele.

Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy.

Five novel mutations in the gene for human blood coagulation factor V associated with type I factor V deficiency.

Splice site mutation in the human protein C gene associated with venous thrombosis: demonstration of exon skipping by ectopic transcript analysis.

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Splice site mutation in the human protein C gene associated with venous thrombosis: demonstration of exon skipping by ectopic transcript analysis.