A locus for autosomal dominant progressive non-syndromic hearing loss, DFNA27, is on chromosome 4q12-13.1.

We ascertained a large North American family, LMG2, segregating progressive, non-syndromic, sensorineural hearing loss. A genome-wide scan identified significant evidence for linkage (maximum logarithm of the odds (LOD) score = 4.67 at theta = 0 for D4S398) to markers in a 5.7-cM interval on chromosome 4q12-13.1. The DFNA27 interval spans 8.85 Mb and includes at least 61 predicted and 8 known genes. We sequenced eight genes and excluded them as candidates for the DFNA27 gene.

A five-generation family with late-onset progressive hereditary hearing impairment due to cochleosaccular degeneration.

Cochleosaccular dysplasia or degeneration (Scheibe degeneration) is considered the most common cause of profound congenital hearing impairment, and accounts for approximately 70% of cases 2 with hereditary deafness. A five-generation family with hereditary hearing impairment associated with cochleosaccular degeneration has recently been identified. The diagnosis of classical Scheibe degeneration was based on histopathological findings in the temporal bones of the proband, a 61-year-old profoundly deaf male. Auditory structures in the brainstem of the proband were also studied. Twenty-two members of the family were contacted for surveys and blood samples. Of these, 6 males and 2 females have hearing impairment. Complete audiological evaluation was done on 12 family members, and prior audiologic records of the proband and affected family members were available for study. Affected family members suffer a mild bilateral high-frequency hearing loss during childhood and adolescence, and progress to moderate-to-profound deafness in the second and third decades of life. The family is suitable for linkage analysis and does not map to previously reported loci harboring autosomal dominant, nonsyndromic hereditary hearing impairment genes. The genetic study of this family will be helpful in identifying the genes which, when mutated, result in Scheibe degeneration.

Genotype-phenotype correlations in type 1 Waardenburg syndrome.

Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder characterized by dystopia canthorum, sensorineural deafness, and pigmentary disturbances. Previous work has linked the disease to PAX3, a transcription factor with two highly conserved DNA binding motifs: a paired box and a homeobox. Several mutations within the paired box of PAX3 have been reported. We have identified the first two mutations within the homeobox in two different families. Herein, we report the phenotypic expression of WS1 in these two families and explore the implications for possible genotype-phenotype correlations. The phenotypic expression was variable within and between the families. Sensorineural hearing loss was present in 71% of affected individuals. Spectrum of hearing loss included unilateral high frequency (>4000 Hz), profound unilateral hearing loss, and bilateral profound hearing loss. The severity of hearing impairment varied significantly within and among families. Phenotypically, these two WS1 families with mutations within the PAX3 homeobox could not be differentiated from those families with paired box mutations. More precise genotype/phenotype correlation may be possible when additional mutations are described throughout the PAX3 gene.

A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3.

Mapping genes for nonsyndromic hereditary hearing impairment may lead to identification of genes that are essential for the development and preservation of hearing. We studied a family with autosomal dominant, progressive, low frequency sensorineural hearing loss. Linkage analysis employing microsatellite polymorphic markers revealed a fully linked marker (D4S126) at 4p16.3, a gene-rich region containing IT15, the gene for Huntington's disease (HD). For D4S126, the logarithm-of-odds (lod) score was 3.64 at theta = 0, and the overall maximum lod score was 5.05 at theta = 0.05 for D4S412. Analysis of recombinant individuals maps the disease gene to a 1.7 million base pair (Mb) region between D4S412 and D4S432. Genes for two types of mutant mice with abnormal cochleovestibular function, tilted (tlt) and Bronx waltzer (bv), have been mapped to the syntenic region of human 4p16.3 on mouse chromosome 5. Further studies with the goals of cloning a gene for autosomal nonsyndromic hearing impairment and identifying the murine homologue may explain the role of this gene in the development and function of the cochlea.

Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families.

Waardenburg syndrome is an autosomal dominant disorder characterized by sensorineural deafness and pigmentary disturbances. Previous work has linked the disease to PAX3 on chromosome 2, and several mutations within the highly conserved paired-box and octapeptide motifs, but not the homeobox, have been reported. In this report, we have used the published cDNA sequence to further define the genomic structure of PAX3, using inverse PCR. We have identified exon/intron boundaries between exons 5 and 6 and between exons 6 and 7. Further, we have identified the first two mutations within the homeobox in two different families with type 1 Waardenburg syndrome. The first is a point mutation (G-->T) at the first base of exon 6, which substitutes phenylalanine for valine. In another family, we have identified a point mutation (C-->G) within the homebox, in exon 6, which substitutes a glycine for arginine at a highly conserved site. The homeodomain is important in binding of DNA and in effecting transcriptional control. These mutations likely result in structural change within the homeodomain that either change the DNA-binding specificity of the homedomain or reduce the affinity of the PAX3 protein for DNA. These homeodomain mutations should aid in elucidating the role of the homeodomain in the function of the PAX3 protein.

Finding the gene(s) for Waardenburg syndrome(s).

Waardenburg syndrome is a recognizable disorder characterized by autosomal dominant inheritance of pigmentary abnormalities of the eyes, hair, and skin sometimes associated with congenital hearing impairment. At least two different types of Waardenburg syndrome have been described. The different types of Waardenburg syndrome are differentiated as follows: type I, with dystopia canthorum; type II, without dystopia canthorum; and type III, without dystopia, with unilateral eyelid ptosis and skeletal abnormalities. Results of pooled linkage analysis done by a consortium of investigators suggests that Waardenburg syndrome type I is genetically heterogeneous, meaning that there is probably more than one genotype that can be associated with the findings typical of the syndrome. A mutated gene that can cause Waardenburg syndrome type I has been discovered. Either a single base pair substitution or an 18 base pair deletion in exon 2 has been found in affected individuals but is not found in unaffected members. Most likely, the mutated gene causes a perturbation in DNA binding of a paired domain, in turn having an effect on the regulation of other genes so the development and spatial orientation of cells and structures derived from the neural crest are affected. Forty years after Waardenburg syndrome was first described, a mutant gene has been found that is known to cause the syndrome. The process of discovery that has transpired in the time from syndrome description to gene identification has been one of steady progress and interdisciplinary cooperation.(ABSTRACT TRUNCATED AT 250 WORDS)