Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.

Autor: Faridi R; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, Maryland, USA., Yousaf R; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, Maryland, USA., Gu S; Auditory Development and Restoration Program, NIDCD, NIH, Bethesda, Maryland, USA., Inagaki S; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, Maryland, USA., Turriff AE; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., Pelstring K; Division of Medical Genetics, Dayton Children's Hospital, Dayton, Ohio, USA., Guan B; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., Naik A; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., Griffith AJ; Otolaryngology Branch, NIDCD, NIH, Bethesda, Maryland, USA., Adadey SM; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana.; Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa., Aboagye ET; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana.; Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa., Awandare GA; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana., Morell RJ; Genomics and Computational Biology Core, NIDCD, NIH, Bethesda, Maryland, USA., Tsilou E; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., Noyes AG; GeneDx, Inc., Gaithersburg, Maryland, USA., Sulmonte LAG; GeneDx, Inc., Gaithersburg, Maryland, USA., Wonkam A; Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.; McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Schrauwen I; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, New York, USA., Leal SM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, New York, USA.; Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA., Azaiez H; Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA., Brewer CC; Otolaryngology Branch, NIDCD, NIH, Bethesda, Maryland, USA., Riazuddin S; Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore, Pakistan., Hufnagel RB; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., Hoa M; Auditory Development and Restoration Program, NIDCD, NIH, Bethesda, Maryland, USA., Zein WM; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, Maryland, USA., de Dios JK; Division of Medical Genetics, Dayton Children's Hospital, Dayton, Ohio, USA., Friedman TB; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2023 Jun; Vol. 103 (6), pp. 699-703. Date of Electronic Publication: 2023 Mar 13.
DOI: 10.1111/cge.14312
Abstrakt: Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) and c.149C > G, p.(Thr50Ser). In Family 2, two sisters were found to be compound heterozygous for LRP2 variants, p.(Tyr3933Cys) and an experimentally confirmed c.7715 + 3A > T consensus splice-altering variant. In Family 3, the proband is compound heterozygous for a consensus donor splice site variant LRP2: c.8452_8452 + 1del and p.(Cys3150Tyr). In mouse cochlea, Lrp2 is expressed abundantly in the stria vascularis marginal cells demonstrated by smFISH, single-cell and single-nucleus RNAseq, suggesting that a deficiency of LRP2 may compromise the endocochlear potential, which is required for hearing. LRP2 variants have been associated with Donnai-Barrow syndrome and other multisystem pleiotropic phenotypes different from the phenotypes of the four cases reported herein. Our data expand the phenotypic spectrum associated with pathogenic variants in LRP2 warranting their consideration in individuals with a combination of hereditary hearing loss and retinal dystrophy.
(© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
Databáze: MEDLINE
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