@article {615, title = {Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.}, journal = {PLoS Genet}, volume = {14}, year = {2018}, month = {2018 08}, pages = {e1007504}, abstract = {

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

}, keywords = {Animals, Asian Continental Ancestry Group, Cell Line, Chloride Channels, Cytoplasm, Eye Proteins, HEK293 Cells, Homozygote, Humans, Mice, Mice, Knockout, Mutation, Missense, Pakistan, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007504}, author = {Li, Lin and Jiao, Xiaodong and D{\textquoteright}Atri, Ilaria and Ono, Fumihito and Nelson, Ralph and Chan, Chi-Chao and Nakaya, Naoki and Ma, Zhiwei and Ma, Yan and Cai, Xiaoying and Zhang, Longhua and Lin, Siying and Hameed, Abdul and Chioza, Barry A and Hardy, Holly and Arno, Gavin and Hull, Sarah and Khan, Muhammad Imran and Fasham, James and Harlalka, Gaurav V and Michaelides, Michel and Moore, Anthony T and Coban Akdemir, Zeynep Hande and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and Qamar, Raheel and Salman, Ahmed and Chilton, John and Self, Jay and Ayyagari, Radha and Kabir, Firoz and Naeem, Muhammad Asif and Ali, Muhammad and Akram, Javed and Sieving, Paul A and Riazuddin, Sheikh and Baple, Emma L and Riazuddin, S Amer and Crosby, Andrew H and Hejtmancik, J Fielding} } @article {403, title = {Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 03 07}, pages = {44185}, abstract = {

Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56\% (95\% CI: 46.52-65.24\%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.

}, keywords = {Albinism, Oculocutaneous, Alleles, Female, Gene Frequency, Humans, Male, Membrane Transport Proteins, Mutation, Missense, Pakistan}, issn = {2045-2322}, doi = {10.1038/srep44185}, author = {Shahzad, Mohsin and Yousaf, Sairah and Waryah, Yar M and Gul, Hadia and Kausar, Tasleem and Tariq, Nabeela and Mahmood, Umair and Ali, Muhammad and Khan, Muzammil A and Waryah, Ali M and Shaikh, Rehan S and Riazuddin, Saima and Ahmed, Zubair M} } @article {117, title = {Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {29}, year = {2016}, month = {2016 Mar}, pages = {231-5}, keywords = {Adolescent, Adult, Alleles, Child, Child, Preschool, Female, Hermanski-Pudlak Syndrome, Humans, Infant, Male, Membrane Proteins, Middle Aged, Pakistan, Pedigree}, issn = {1755-148X}, doi = {10.1111/pcmr.12438}, author = {Yousaf, Sairah and Shahzad, Mohsin and Kausar, Tasleem and Sheikh, Shakeel A and Tariq, Nabeela and Shabbir, Asra S and Ali, Muhammad and Waryah, Ali M and Shaikh, Rehan S and Riazuddin, Saima and Ahmed, Zubair M} } @article {142, title = {Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {28}, year = {2015}, month = {2015 Nov}, pages = {730-5}, abstract = {

Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor of the melanocyte{\textquoteright}s plasma membrane, is a major determinant of skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers the cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing to identify causative alleles in Pakistani families with skin and hair hypopigmentation. Six MC1R mutations segregated with the phenotype in seven families, including a p.Val174del in-frame deletion and a p.Tyr298* nonsense mutation, that were analyzed for function in heterologous HEK293 cells. p.Tyr298* MC1R showed no agonist-induced signaling to the cAMP or ERK pathways, nor detectable agonist binding. Conversely, signaling was comparable for p.Val174del and wild-type in HEK cells overexpressing the proteins, but binding analysis suggested impaired cell surface expression. Flow cytometry and confocal imaging studies revealed reduced plasma membrane expression of p.Val174del and p.Tyr298*. Therefore, p.Tyr298* was a total loss-of-function (LOF) allele, while p.Val174del displayed a partial LOF attribute.

}, keywords = {Alleles, Family, Female, Humans, Hypopigmentation, Male, Mutation, Pakistan, Pedigree, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1755-148X}, doi = {10.1111/pcmr.12400}, author = {Shahzad, Mohsin and Sires Campos, Julia and Tariq, Nabeela and Herraiz Serrano, Cecilia and Yousaf, Rizwan and Jim{\'e}nez-Cervantes, Celia and Yousaf, Sairah and Waryah, Yar M and Dad, Haseeb A and Blue, Elizabeth M and Sobreira, Nara and L{\'o}pez-Gir{\'a}ldez, Francesc and Kausar, Tasleem and Ali, Muhammad and Waryah, Ali M and Riazuddin, Saima and Shaikh, Rehan S and Garc{\'\i}a-Borr{\'o}n, Jos{\'e} C and Ahmed, Zubair M} }