Bonne-Tamir et al. (1996) conducted a genome search for linkage in a large, inbred Palestinian family segregating an autosomal recessive form of non-syndromic deafness. In this family, the defective gene, DFNB10, is located in a 12-cM region near the telomere of chromosome 21. This genetic distance corresponds to <2 .4 mbp. five marker loci typed from this region gave maximum lod scores>/=3. Most of the affected members of this family resulted from consanguineous unions, indicating that they are homozygous for the same genetic defect. Homozygosity of marker alleles was evident for only the most telomeric marker, D21S1259, suggesting that DFNB10 is closest to this locus. Bonne-Tamir et al. (1996) claimed that this was the first evidence, at this location, for a gene that is involved in the development or maintenance of hearing.

In a Palestinian family with the congenital form of deafness designated DFNB10, Scott et al. (2001) identified a mutation consisting of an 8-bp deletion and insertion of 18 complete beta-satellite repeat monomers, which are normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes. The mobile nature of repetitive sequences on the short arms of acrocentric chromosomes is well documented. Although chromosomal rearrangements involving beta-satellites had been described, this was the first description of beta-satellite insertion into an active gene resulting in a pathogenic state. This was also the first description of a protease involved in hearing loss.

Walsh et al. (2006) undertook a study to identify the genes responsible for inherited hearing loss, by linkage scan using microsatellite markers in 156 affected individuals and their families. The authors were able to identify a Palestinian family with mutation in the TMPRSS3 gene. Ten living members in the family were diagnosed with prelingual, bilateral, severe to profound hearing loss. All of them were found to be homozygous at markers D21S1255 and GT (42.667), flanking TMPRSS3. Sequencing of the TMPRSS3 gene revealed a homozygous mutation 988delA in all affected individuals. All unaffected members of the family were found to be either heterozygous carriers of this mutation or wild type. The mutation leads to a frameshift in exon 10, introducing a stop codon at position 357. Walsh et al. (2006) predicted that truncation of the polypeptide at this position would eliminate the active proteolytic domain of the protein, and would thus, abrogate TMPRSS3 activity. Three other hearing impaired Palestinian individuals, unrelated to this family, were also found to be homozygous for the mutation.

Shahin et al. (2010) carried out a molecular study to identify the genes responsible for inherited hearing loss, by using high-density SNP arrays to genotype the DNA of 155 relatives (including: 78 patients, 28 of their hearing siblings, and 49 parents) from 20 Palestinian consanguineous families with prelingual bilateral autosomal recessive non-syndromic hearing loss (NSHL). In 14 families, Shahin et al. (2010) identified the allele responsible for hearing loss by screening a single candidate gene, known to be associated with hearing loss, in the longest homozygous region. They identified a nonsense mutation (c.783T>A; p.Cys194STOP) in the TMPRSS3 gene in one family with three affected sibs (one male and two females). The predicted truncation is within the scavenger receptor cysteine-rich domain, which is N-terminal of the serine protease domain, and hence likely to abolish protease activity. Shahin et al. (2010) noted that this mutation represented the third different TMPRSS3 truncating allele discovered in Palestinian families.

In individuals with congenital nonsyndromic autosomal recessive deafness (DFNB10) in a consanguineous Tunisian family, Masmoudi et al. (2001) found homozygosity for a G-to-C transversion in the TMPRSS3 gene, leading to a trp251-to-cys (W251C) missense mutation. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C may lead to a structural rearrangement affecting the active site his257. In addition, in a consanguineous Tunisian family, Masmoudi et al. (2001) found that individuals with congenital nonsyndromic autosomal recessive deafness (DFNB10) were homozygous for a 1221C-T transition in the TMPRSS3 gene, leading to a pro404-to-leu missense mutation. Comparative protein modeling of the TMPRSS3 protease domain predicted that P404L may alter the geometry of the active site loop and therefore affect the serine protease activity.