Biallelic ATP2B1 variants as a likely cause of a novel neurodevelopmental malformation syndrome with primary hypoparathyroidism.

Autor: Yap P; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand. patricky@adhb.govt.nz.; Genetic Health Service New Zealand - Northern hub, Auckland, New Zealand. patricky@adhb.govt.nz., Riley LG; Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and The Children's Medical Research Institute, Sydney, NSW, 2145, Australia.; Specialty of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia., Kakadia PM; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.; Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand., Bohlander SK; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.; Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand., Curran B; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand., Rahimi MJ; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, 04103, Germany., Alburaiky S; Genetic Health Service New Zealand - Northern hub, Auckland, New Zealand., Hayes I; Genetic Health Service New Zealand - Northern hub, Auckland, New Zealand., Oppermann H; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, 04103, Germany., Print C; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand., Cooper ST; Specialty of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.; Kids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Sydney, NSW, 2145, Australia.; The Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, NSW, 2145, Australia., Le Quesne Stabej P; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Jan; Vol. 32 (1), pp. 125-129. Date of Electronic Publication: 2023 Nov 06.
DOI: 10.1038/s41431-023-01484-9
Abstrakt: ATP2B1 encodes plasma membrane calcium-transporting-ATPase1 and plays an essential role in maintaining intracellular calcium homeostasis that regulates diverse signaling pathways. Heterozygous de novo missense and truncating ATP2B1 variants are associated with a neurodevelopmental phenotype of variable expressivity. We describe a proband with distinctive craniofacial gestalt, Pierre-Robin sequence, neurodevelopmental and growth deficit, periventricular heterotopia, brachymesophalangy, cutaneous syndactyly, and persistent hypocalcemia from primary hypoparathyroidism. Proband-parent trio exome sequencing identified compound heterozygous ATP2B1 variants: a maternally inherited splice-site (c.3060+2 T > G) and paternally inherited missense c.2938 G > T; p.(Val980Leu). Reverse-transcription-PCR on the proband's fibroblast-derived mRNA showed aberrantly spliced ATP2B1 transcripts targeted for nonsense-mediated decay. All correctly-spliced ATP2B1 mRNA encoding p.(Val980Leu) functionally causes decreased cellular Ca 2+ extrusion. Immunoblotting showed reduced fibroblast ATP2B1. We conclude that biallelic ATP2B1 variants are the likely cause of the proband's phenotype, strengthening the association of ATP2B1 as a neurodevelopmental gene and expanding the phenotypic characterization of a biallelic loss-of-function genotype.
(© 2023. The Author(s).)
Databáze: MEDLINE
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