A Novel TECTA Mutation in a Dutch DFNA8/12 Family Confirms Genotype–Phenotype Correlation

Abstract

A novel TECTA mutation, p.R1890C, was found in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. In early life, presumably congenital, hearing impairment occurred in the midfrequency range, amounting to about 40 dB at 1 kHz. Speech recognition was good with all phoneme recognition scores exceeding 90%. An intact horizontal vestibuloocular reflex was found in four tested patients. The missense mutation is located in the zona pellucida (ZP) domain of a-tectorin. Mutations affecting the ZP domain of a-tectorin are significantly associated with midfrequency hearing impairment. Substitutions affecting other amino acid residues than cysteines show a significant association with hearing impairment without progression. Indeed, in the present family progression seemed to be absent. In addition, the presently identified mutation affecting the ZP domain resulted in a substantially lesser degree of hearing impairment than was previously reported for DFNA8/12 traits with mutations affecting the ZP domain of a-tectorin.

Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer

“…At the protein level, this change, however, does not result in the substitution of an amino acid (p.L1777L; Figure 2a), indicating that the a-tectorin protein encoded by the mutant allele would not differ from the wild-type protein. Although thus far, only missense mutations within the zona pellucida (ZP) domain of a-tectorin have been shown to cause a midfrequency type of hearing impairment, 4 the synonymous change found in exon 16 was still considered to be a candidate causative mutation for a number of reasons. First, the c.5331G4A change segregated with the hearing loss and was not detected in over 250 ethnically matched control alleles (data not shown).…”

“…Depending on the exons carrying the mutation and thus the affected protein domains, TECTA mutations cause either mid-frequency or high-frequency hearing loss. 4 Here, we report on a Dutch family in which individuals suffer from autosomal dominant hearing loss with either a U-shaped or a flat audiogram. Whole-genome SNP genotyping mapped the genetic defect underlying the hearing loss in this family to the DFNA8/12 locus.…”

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…79 Mutations of various parts of a-tectorin lead to HL at different frequencies and lead to specific genotype-phenotype correlations. 71,[80][81][82] TMC1 gene Mutations in the transmembrane cochlear-expressed gene 1 (TMC1), located on chromosome 9q13-21, can also result in both progressive autosomal dominant and autosomal recessive HL (DFNA36 and DFNB7/DFNB11). 83,84 There are eight vertebrate TMC genes on the basis of their sequence homology.…”

TECTA mutations in Japanese with mid-frequency hearing loss affected by zona pellucida domain protein secretion

“…[3][4][5][6][7][8][9][10] This gene encodes a-tectorin, the major component of noncollagenous glycoprotein of the tectorial membrane that consists of an extracellular matrix overlying the organ of corti, contacting the outer cochlear hair cells, and having a role in intracochlear sound transmission. 11 The a-tectorin is composed of three distinct modules: the entactin G1 domain, the zonadhesin (ZA) domain with von Willebrand factor type D repeats and the zona pellucida (ZP) domain.…”