Saadullah Khan

Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction

We mapped a human deafness locus DFNB36 to chromosome 1p36.3 in two consanguineous families segregating recessively inherited deafness and vestibular areflexia. This phenotype co-segregates with either of two frameshift mutations, 1988delAGAG and 2469delGTCA, in ESPN, which encodes a calcium-insensitive actin-bundling protein called espin. A recessive mutation of ESPN is known to cause hearing loss and vestibular dysfunction in the jerker mouse. Our results establish espin as an essential protein for hearing and vestibular function in humans. The abnormal vestibular phenotype associated with ESPN mutations will be a useful clinical marker for refining the differential diagnosis of non-syndromic deafness.

FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia

Background  Isolated nail dysplasia is rare and has been reported in only a small number of families.

Novel mutations in natriuretic peptide receptor-2 gene underlie acromesomelic dysplasia, type maroteaux

BackgroundNatriuretic peptides (NPs) are peptide hormones that exert their biological actions by binding to three types of cell surface natriuretic peptide receptors (NPRs). The receptor NPR-B binding C-type natriuretic peptide (CNP) acts locally as a paracrine and/or autocrine regulator in a wide variety of tissues. Mutations in the gene NPR2 have been shown to cause acromesomelic dysplasia-type Maroteaux (AMDM), an autosomal recessive skeletal disproportionate dwarfism disorder in humans.MethodsIn the study, presented here, genotyping of six consanguineous families of Pakistani origin with AMDM was carried out using polymorphic microsatellite markers, which are closely linked to the gene NPR2 on chromosome 9p21-p12. To screen for mutations in the gene NPR2, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected and unaffected individuals of the families and sequenced.ResultsSequence analysis of the gene NPR2 identified a novel missence mutation (p.T907M) in five families, and a splice donor site mutation c.2986 + 2 T > G in the other family.ConclusionWe have described two novel mutations in the gene NPR2. The presence of the same mutation (p.T907M) and haplotype in five families (A, B, C, D, E) is suggestive of a founder effect.

A novel homozygous missense mutation in WNT10B in familial split‐hand/foot malformation

Khan S, Basit S, Zimri FK, Ali N, Ali G, Ansar M, Ahmad W. A novel homozygous missense mutation in WNT10B in familial split‐hand/foot malformation.

Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A

Background Postaxial polydactyly (PAP) type A is characterised by well-formed functionally developed 5th digit duplication in hands and/or feet. It is genetically heterogeneous condition, inherited both in autosomal recessive and dominant manners. To date one autosomal recessive and four autosomal dominant loci have been mapped on human chromosomes. In the present study we have investigated a consanguineous Pakistani family segregating autosomal recessive PAP type A to identify the gene responsible for this phenotype. Methods Whole exome sequencing combined with homozygosity mapping and array comparative genomic hybridisation (aCGH) analysis was used to search for a genetic cause of PAP type A in the present study. Results Exome sequencing identified a missense mutation (c.1420C>T; p.Thr474Ile) in all the affected individuals of the family, in the gene ZNF141, mapped to the telomeric region on chromosome 4p16.3. Conclusion This study revealed involvement of a zinc finger gene ZNF141 in causing autosomal recessive PAP type A, which may open up interesting perspectives into the function of this protein in limb development.

Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan

Background.  Autosomal recessive hypotrichosis/woolly hair is a rare genetic hair loss disorder characterized by sparse scalp hair/woolly hair, sparse to absent eyebrows and eyelashes, sparse axillary and body hair in affected individuals. This form of hair loss results from mutations in either LPAR6 or LIPH gene.

Novel homozygous mutations in the genes ARL6 and BBS10 underlying Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder resulting from structural and functional defects in numerous organs. Frequent manifestations reported in the syndrome include obesity, renal dysplasia, cognitive impairment, postaxial polydactyly, pigmentary retinal degeneration and hypogonadism. To date, 17 genes causing BBS have been identified. Two of these BBS1 and BBS10 are the most frequently mutated genes. The present report describes two consanguineous families (A, B) with clinical manifestations of BBS. Linkage in the family A was established to ARL6 on chromosome 3q11.2, while family B showed linkage to BBS10 on chromosome 12q21.2. Sequence analysis revealed a novel homozygous missense mutation (c.281T>C, p.Ile94Thr) in the gene ARL6 in family A and a nonsense mutation (c.1075C>T, p.Gln359*) in the gene BBS10 in family B. Mutations identified in the present study extend the body of evidence implicating the genes ARL6 and BBS10 in causing Bardet-Biedl syndrome.

Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families

Acromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive skeletal disorder characterized by disproportionate short stature with shortening of the acromesomelic sections of the limbs. AMDM is caused by mutations in the NPR2 gene located on chromosome 9p21‐p12. The gene encodes the natriuretic peptide receptor B (NPR‐B) that acts as an endogenous receptor for C‐type natriuretic peptide (CNP). Both CNP and NPR‐B are considered as important regulators of longitudinal growth. The study presented here investigated three consanguineous families (A, B, C) segregating AMDM in an autosomal recessive manner. Linkage in the families was established to the NPR2 gene on chromosome 9p12‐21. Sequence analysis of the gene revealed two novel missense variants (p.Arg601Ser; p.Arg749Trp) in two families and a previously reported splice site variant (c.2986+2T>G) in the third family.

Novel TMPRSS3 variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.

Lee K, Khan S, Islam A, Ansar M, Andrade PB, Kim S, Santos‐Cortez RLP, Ahmad W, Leal SM. Novel TMPRSS3 variants in Pakistani families with autosomal recessive non‐syndromic hearing impairment.

A novel splice site mutation in gene C2orf37 underlying Woodhouse–Sakati syndrome (WSS) in a consanguineous family of Pakistani origin

Woodhouse-Sakati Syndrome (WSS) is a rare autosomal recessive multisystemic disorder that is marked by hypogonadism, alopecia, intellectual disability, deafness, diabetes mellitus and progressive extrapyramidal defects. Mutations in the gene C2orf37 are the cause of Woodhouse-Sakati syndrome. In the present study, a four-generation consanguineous family with clinical manifestations of WSS was ascertained from a remote region of Pakistan. Linkage in the family was tested using microsatellite markers linked to several genes involved in producing WSS related phenotypes. Linkage in the family was established to the gene C2orf37, mapped on chromosome 2q22.3-2q35. DNA sequence analysis revealed a novel splice site mutation involving a homozygous G→A transition in the splice donor site of intron 3 (c.321+1G>A) of C2orf37. This study presents a first report of Woodhouse-Sakati syndrome identified in Pakistani population.