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A Transcriptomic Analysis and shRNA Screen for Intracellular Ion Channels and Transporters Regulating Pigmentation
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Donald C. Koroma, Salwa Y. Hafez, Elena Oancea
Defects in melanosomal function result in albinism, characterized by total or partial lack of pigment in the skin, hair, and eyes. Albinism occurs at a frequency of ~1:20,000 in the US, with significantly higher incidence (>1:1,400) in Africa (Luande, Henschke, and Mohammed 1985). The lack of pigment in albinism causes severe visual impairment and elevated susceptibility to skin cancers. Of the seven types of oculocutaneous albinism identified so far, OCA1–7 (Montoliu et al. 2014), five types (OCA1–4 and OCA6) are caused by mutations in genes encoding putative melanosomal transmembrane proteins. Three of these five transmembrane proteins (OCA2, 4, and 6) have the topology of an ion channel or transporter (predicted by UniProtKB, www.uniprot.org) with unknown function, while the protein encoded by the gene mutated in OCA5 is yet to be identified (Kausar et al. 2013). In addition to mutations in melanocyte-specific genes that lead to albinism, there are other identified mutations that cause diseases associated with hypopigmentation or hyperpigmentation (Chow et al. 2007, Bowman et al. 2019, Wang et al. 2015), suggesting that proteins that are not melanocyte-specific can also regulate pigmentation.
Oculocutaneous albinism
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Mira Kadurina, Anastasiya A. Chokoeva, Torello Lotti
The two main affected organs in albinism are the skin and eyes. However, patients with ocular albinism may also have skin problems, while patients with cutaneous albinism show ocular findings quite often.7 The degree of hypo- and depigmentation varies widely between the different types of albinism based on the activity of tyrosinase. Patients with completely inactive tyrosinase are totally depigmented at birth with no melanin in irises and retina, leading to red reflex and severe ocular defects. Their hair is totally white, and they never get darker or tanned. If there is some degree of functional tyrosinase, it may lead to some hair color, seen in patients with the so-called OCA1-b form of albinism, where a mild degree of skin pigmentation may develop later in life. One extremely rare form of OCA1-B is the so-called “temperature-sensitive OCA1-b,” where tyrosinase is only active when the temperature is lower than the body temperature, resulting in some degree of peripheral pigmentation of the extremities.1,3,7
Oculocutaneous albinism type 1B associated with a functionally significant tyrosinase gene polymorphism detected with Whole Exome Sequencing
Published in Ophthalmic Genetics, 2021
Rodrigo Mendez, Sumaiya Iqbal, Sebastián Vishnopolska, Cinthia Martinez, Glenda Dibner, Rocio Aliano, Jonathan Zaiat, Germán Biagioli, Cecilia Fernandez, Adrian Turjanski, Arthur J Campbell, Graciela Mercado, Marcelo A. Marti
Oculocutaneous Albinism (OCA) is a genetically heterogeneous congenital disorder caused by mutations in up to 24 genes identified to date. OCA type 1 (OCA1) is a recessive inherited condition caused by a mutation in the Tyrosinase (TYR) gene, which codifies for a transmembrane enzyme (TYR, OMIM: 606933) involved in the first and rate-limiting step of melanin metabolism from tyrosine in the melanosomes (1). This protein is widely distributed among animals, plants, and fungi, and the active site is highly conserved across the different species (2). Tyrosinase contains several functional domains: an epidermal growth factor (EGF)-like domain, and a transmembrane (TM) domain containing a pair of coupled copper ions (CuA and CuB) each coordinated to three conserved Histidine residues (3). This dicopper center is located at the bottom of putative substrate-binding pocket, which is created by several hydrophobic residues (4).
The challenges faced by clinicians diagnosing and treating infantile nystagmus Part I: diagnosis
Published in Expert Review of Ophthalmology, 2021
Eleni Papageorgiou, Irene Gottlob
Albinism has been traditionally divided into oculocutaneous albinism (OCA) or ocular albinism (OA) on the basis of phenotypical features. However, the recent advances in molecular genetics have expanded the classification of various albinism subtypes based on the genetic profile of patients. Oculocutaneous albinism (OCA) is characterized by disruption of melanin biosynthesis, resulting in a lack of pigmentation in the eyes, skin, and hair [80]. Oculocutaneous albinism is a group of autosomal recessive disorders which are classified into seven types according to the affected gene [81]. OCA1 is caused by mutations in the tyrosinase gene (TYR) and is present in most populations except African-Americans [81]. It can present with either a complete lack of melanin production (OCA1A) or partial melanin production (OCA1B). Mutations in OCA2, TYRP1, SLC45A2, SLC24A5, and LRMDA have been attributed to subtypes OCA2, OCA3, OCA4, OCA6, and OCA7, respectively [81]. OCA2 and OCA3 are more common in African populations and are milder forms of albinism. OCA4 is another mild form of albinism that has been recently found in Turkish, Japanese, German, and Korean patients [81]. For OCA6 and OCA7 there are only case reports in a Chinese family and a consanguineous Faroese family. OCA5 is very rare, and has been only mentioned in a case report of a Pakistani family. The OCA5 locus is at 4q24, but the causative gene has not yet been identified [82].
Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease
Published in Ophthalmic Genetics, 2018
Claudia Yahalom, Michal Macarov, Galit Lazer-Derbeko, Gheona Altarescu, Tal Imbar, Jordana H. Hyman, Talia Eldar-Geva, Anat Blumenfeld
One of the families with RP in our study had a history of autosomal recessive RP caused by the most prevalent mutation in the FAM161A gene (MIM: 613596); this mutation is a major cause of RP in the vicinity of Jerusalem(21). In another family with a history of LCA, the affected family members were homozygous for the c.387delC (p.P130Lfs*35) mutation in the GUCY2D gene. This mutation has not been published previously; however, it has been listed as a pathogenic variant in the NCBI database ClinVar(38) and is reported here for the first time. The second most common diagnosis within the families who underwent PGD was albinism, present in ten of the 35 families. The affected family members in all ten of these families had a mutation(s) in the TYR gene associated with a severe form of OCA1. One possible explanation for the relatively high prevalence of albinism among the families who underwent PGD at our hospital is that the national referral center for albinism is located at the Michaelson Institute in the Department of Ophthalmology at Hadassah-Hebrew University Medical Center in Israel. Patients with albinism from around the country are referred to our center for diagnosis and treatment. The majority of the mutations in our families cause OCA1A(39) and have been reported previously among Israeli Jewish populations(40). Among the ten families with OCA in our cohort, the affected members of four families had visual acuity of 20/200, and the visual acuity of the affected members in the other six families ranged from 20/80 to 20/160.