Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14

Abstract In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygo...

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Autores principales:	Stephen F. Pastore, Tahir Muhammad, Ricardo Harripaul, Rebecca Lau, Muhammad Tariq Masood Khan, Muhammad Ismail Khan, Omar Islam, Changsoo Kang, Muhammad Ayub, Musharraf Jelani, John B. Vincent
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2ba8a4534d8c463e94a9689d1d8a2244
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spelling	oai:doaj.org-article:2ba8a4534d8c463e94a9689d1d8a22442021-12-05T12:14:20ZBiallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH1410.1038/s41598-021-02599-z2045-2322https://doaj.org/article/2ba8a4534d8c463e94a9689d1d8a22442021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02599-zhttps://doaj.org/toc/2045-2322Abstract In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.Stephen F. PastoreTahir MuhammadRicardo HarripaulRebecca LauMuhammad Tariq Masood KhanMuhammad Ismail KhanOmar IslamChangsoo KangMuhammad AyubMusharraf JelaniJohn B. VincentNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stephen F. Pastore Tahir Muhammad Ricardo Harripaul Rebecca Lau Muhammad Tariq Masood Khan Muhammad Ismail Khan Omar Islam Changsoo Kang Muhammad Ayub Musharraf Jelani John B. Vincent Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
description	Abstract In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.
format	article
author	Stephen F. Pastore Tahir Muhammad Ricardo Harripaul Rebecca Lau Muhammad Tariq Masood Khan Muhammad Ismail Khan Omar Islam Changsoo Kang Muhammad Ayub Musharraf Jelani John B. Vincent
author_facet	Stephen F. Pastore Tahir Muhammad Ricardo Harripaul Rebecca Lau Muhammad Tariq Masood Khan Muhammad Ismail Khan Omar Islam Changsoo Kang Muhammad Ayub Musharraf Jelani John B. Vincent
author_sort	Stephen F. Pastore
title	Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
title_short	Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
title_full	Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
title_fullStr	Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
title_full_unstemmed	Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
title_sort	biallelic inheritance in a single pakistani family with intellectual disability implicates new candidate gene rdh14
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2ba8a4534d8c463e94a9689d1d8a2244
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Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14

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