Novel mutation in the homeobox domain of transcription factor POU3F4 associated with profound sensorineural hearing loss.

BACKGROUND: Hearing loss affects 1 to 3 in 1,000 newborns, with 50% of these cases because of genetic causes. The majority of these are nonsyndromic (70%), and 2% are X linked. So far, 6 different X-linked loci have been mapped, but the causative gene POU3F4 has been identified only for the Locus DFN3. Clinical features of DFN3 often include a mixed, progressive hearing loss, temporal bone anomalies, and stapes fixation. POU3F4 belongs to a subfamily of transcription factors, which are characterized by 2 conserved deoxyribonucleic acid-binding domains, a POU and a HOX domain, both helix-turn-helix structural deoxyribonucleic acid-binding motifs.Several reports have described mutations of POU3F4 in patients with hearing loss and temporal bone abnormalities. In this study, we describe the clinical features and genetic analysis of a male child from a German family with congenital deafness and a novel POU3F4 mutation. METHOD: Mutational analysis of the affected individual and first-degree relatives was performed using direct sequencing of the coding exon and intron transitions of POU3F4. RESULT: The patient (II-1) had profound hearing loss, a severely dysplastic cochlea, and cerebrospinal fluid gusher during cochlear implantation. Sequence analysis of all family members demonstrated a novel missense mutation at nucleotide position 973, thymine to adenine (c.973 T>A), p.W325R in the patient (II-1), the mother (I-2), and sisters (II-2, II-3) heterozygous. The father (I-1) is not a carrier of the mutation. Conservation of the affected amino acid residue was seen across a number of different species. CONCLUSION: We identified a novel mutation in the third helix of the HOX domain of the POU3F4 transcription factor associated with congenital hearing loss.

Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome: Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene.

About one to three of a 1,000 neonates are afflicted at birth with a serious hearing impairment, with about half of the cases due to genetic causes. Genetic causes of hearing impairment are very heterogeneous. About half of all cases of genetically caused nonsyndromic hearing loss can be ascribed to mutations in the GJB2 gene (connexin 26) and to deletions in the GJB6 gene(connexin 30). Thus far, about 90 different mutations have been identified in the GJB2 gene, of which the majority are autosomal recessive. Ten mutations are autosomal dominant and are in most cases associated with various skin diseases: the keratitis-ichthyosis-deafness (KID) syndrome, Vohwinkel syndrome and palmoplantar keratoderma with deafness. To date, the following mutations have been identified which lead to the Palmoplantar Keratoderma syndrome with deafness; Gly59Ala, Gly59Arg, His73Arg, Arg75Trp, and Arg75Gln. We are reporting on four patients with severe hearing impairment. They are members of three unrelated families, who are carriers of mutations Arg75Trp or Arg75Gln, but unlike patients of other publications, do not all present with Palmoplantar Keratoderma syndrome. Our investigations document additional evidence for the correlation between the cited mutations in the GJB2 gene and a syndromic hearing impairment with palmoplantar keratoderma.

Genetic variants of the promoter of the heme oxygenase-1 gene and their influence on cardiovascular disease (the Ludwigshafen Risk and Cardiovascular Health study).

BACKGROUND: Heme oxygenase-1 is an inducible cytoprotective enzyme which handles oxidative stress by generating anti-oxidant bilirubin and vasodilating carbon monoxide. A (GT)n dinucleotide repeat and a -413A>T single nucleotide polymorphism have been reported in the promoter region of HMOX1 to both influence the occurrence of coronary artery disease and myocardial infarction. We sought to validate these observations in persons scheduled for coronary angiography. METHODS: We included 3219 subjects in the current analysis, 2526 with CAD including a subgroup of CAD and MI (n = 1339) and 693 controls. Coronary status was determined by coronary angiography. Risk factors and biochemical parameters (bilirubin, iron, LDL-C, HDL-C, and triglycerides) were determined by standard procedures. The dinucleotide repeat was analysed by PCR and subsequent sizing by capillary electrophoresis, the -413A>T polymorphism by PCR and RFLP. RESULTS: In the LURIC study the allele frequency for the -413A>T polymorphism is A = 0,589 and T = 0,411. The (GT)n repeats spread between 14 and 39 repeats with 22 (19.9%) and 29 (47.1%) as the two most common alleles. We found neither an association of the genotypes or allelic frequencies with any of the biochemical parameters nor with CAD or previous MI. CONCLUSION: Although an association of these polymorphisms with the appearance of CAD and MI have been published before, our results strongly argue against a relevant role of the (GT)n repeat or the -413A>T SNP in the HMOX1 promoter in CAD or MI.