Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population

Shahzad, Mohsin; Campos, Julia Sirés; Tariq, Nabeela; Serrano, Claudia; Yousaf, Rizwan; Jiménez‐Cervantes, Celia; Yousaf, Sairah; Waryah, Yar Muhammad; Dad, Haseeb A.; Blue, Elizabeth; Sobreira, Nara; López-Giráldez, Francesc; Kausar, Tasleem; Ali, Muhammad; Waryah, Ali Muhammad; Riazuddin, Saima; Shaikh, Rehan Sadiq; García‐Borrón, José C.; Ahmed, Zubair M.

doi:10.1111/pcmr.12400

Cited by 4 publications

(2 citation statements)

References 14 publications

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“…To further refine the prevalence estimates, we reviewed the alleles frequencies in known albinism genes among our larger cohort of 143 families, including 48 previously reported families ( Fig. 5B ) 5 30 31 32 33 and in published literature ( Table S1 ). TYR and OCA2 alleles are the frequent cause of OCA in Pakistanis ( Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

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Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population

Shahzad

Yousaf

Waryah

et al. 2017

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

“…Primers ( Table S4 ) covering the coding regions of the TYR, OCA2, TYRP1 and SLC45A2 genes were designed in primer3 software ( http://bioinfo.ut.ee/primer3-0.4.0/primer3/input.htm ) for Sanger sequencing and segregation analysis. PCR amplification, cleaning, and sequencing reactions were performed as previously described 30 32 .…”

Section: Methodsmentioning

confidence: 99%

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population

Shahzad

Yousaf

Waryah

et al. 2017

Sci Rep

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MC1R signaling. Intracellular partners and pathophysiological implications

Herráiz

García‐Borrón

Jiménez‐Cervantes

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

102

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The melanocortin-1 receptor (MC1R) preferentially expressed in melanocytes is best known as a key regulator of the synthesis of epidermal melanin pigments. Its paracrine stimulation by keratinocyte-derived melanocortins also activates DNA repair pathways and antioxidant defenses to build a complex, multifaceted photoprotective response. Many MC1R actions rely on cAMP-dependent activation of two transcription factors, MITF and PGC1α, but pleiotropic MC1R signaling also involves activation of mitogen-activated kinases and AKT. MC1R partners such as β-arrestins, PTEN and the E3 ubiquitin ligase MGRN1 differentially regulate these pathways. The MC1R gene is complex and polymorphic, with frequent variants associated with skin phenotypes and increased cancer risk. We review current knowledge of signaling from canonical MC1R, its splice isoforms and natural polymorphic variants. Recently discovered intracellular targets and partners are also discussed, to highlight the diversity of mechanisms that may contribute to normal and pathological variation of pigmentation and sensitivity to solar radiation-induced damage. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

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Whole-exome sequencing confirmation of multiple MC1R variants associated with extensive freckles and red hair: Analysis of a Mongolian family

Araki¹,

Okamura

Munkhbat

et al. 2016

Journal of Dermatological Science

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Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population

Cited by 4 publications

References 14 publications

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population

Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population

MC1R signaling. Intracellular partners and pathophysiological implications

Whole-exome sequencing confirmation of multiple MC1R variants associated with extensive freckles and red hair: Analysis of a Mongolian family

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