Human MYO15A is located on chromosome 17p11.2, has 66 exons and encodes unconventional myosin XVA. Recessive mutations of MYO15A are associated with profound, nonsyndromic hearing loss DFNB3 in humans, and deafness and circling behavior in shaker 2 mice. In the inner ear, this motor protein is necessary for the development of hair cell stereocilia, which are actin-filled projections on the apical surface and the site of mechanotransduction of sound. The longest isoform of myosin XVA has 3,530 amino acid residues. Two isoform classes of MYO15A are distinguished by the presence or absence of 1,203 residues preceding the motor domain encoded by alternatively-spliced exon 2. It is not known whether this large N-terminal extension of myosin XVA is functionally necessary for hearing. We ascertained approximately 600 consanguineous families segregating hereditary hearing loss as a recessive trait and found evidence of linkage of markers at the DFNB3 locus to hearing loss in 38 of these families ascertained in Pakistan (n=30), India (n=6), and Turkey (n=2). In this study, we describe 16 novel recessive mutations of MYO15A associated with severe to profound hearing loss segregating in 20 of these DFNB3-linked families. Importantly, two homozygous mutant alleles-c.3313G>T (p.E1105X) and c.3334delG (p.G1112fsX1124) of MYO15A-located in exon 2 are associated with severe to profound hearing loss segregating in two families. These data demonstrate that isoform 1, containing the large N-terminal extension, is also necessary for normal hearing.

We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72, on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS, ZNRF4 and CAPS. We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68, the only other known deafness locus with statistically significant support for linkage to chromosome 19p.

A novel mesoporous bioactive glass (MBG) of composition 64SiO 2 -26CaO-10P 2 O 5 (mol %) was prepared by hydrothermal method using H 3 PO 4 as a precursor for P 2 O 5 . The effect of use of organic triethylphosphate (TEP) and inorganic H 3 PO 4 in MBG synthesis on glass transition temperature (T g ), crystallinity, morphology and bioactivity of MBGs was studied. Phase purity determination and structural analysis were done using powder X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy, respectively. XRD revealed that MBG prepared from H 3 PO 4 (MBG-H 3 PO 4 ) when sintered at 700°C was partially glassy/amorphous in nature and contained a mixture of crystalline apatite, wollastonite, calcium phosphate and calcium silicate phases. Calcined MBG prepared from TEP (MBG-TEP) contained only wollastonite and calcium silicate phases. Particle size and surface area determined by BET surface area analysis showed higher surface area (310 m 2 g -1 ) for MBG-H 3 PO 4 as compared to MBG-TEP (86 m 2 g -1 ). It also had a smaller particle size (20 nm) and 70 % higher pore volume (0.88 cm 3 g -1 ) for MBG-H 3 PO 4 as compared to MBG-TEP (60 nm particle size and 0.23 cm 3 g -1 pore volume). Thermal studies showed that use of H 3 PO 4 decreases T g and increased DT (difference between T g and crystallization initiation temperature Tc o ). Low T g and high DT also enhanced bioactivity of MBGs. Bioactivity was determined by immersion in a simulated body fluid for varying time intervals for a maximum period of 14 days. It revealed enhanced bioactivity, as evident by the formation of apatite layer on the surface, for MBG-H 3 PO 4 as compared to MBG-TEP. Scanning electron microscopy and FTIR spectroscopy also supported this observation. Antibacterial studies with Escherichia Coli bacteria, MBG-H 3 PO 4 showed better antibacterial behaviour than MBG-TEP.