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Am J Hum Genet. 2018 Jun 7;102(6):1104-1114. doi: 10.1016/j.ajhg.2018.04.006. Epub 2018 May 31.

TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism.

Author information

1
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Japan.
2
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada; Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: david.chitayat@sinaihealthsystem.ca.
3
Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
4
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
5
GeneDx, Gaithersburg, MD 20877, USA.
6
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada.
7
Division of Endocrinology and Metabolism, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
8
Department of Medical Genetics and Genomics, Graduate School of Medical Sciences, Kitasato University, Kanagawa 252-0375, Japan; Division of Genetics and Genomics, Center for Clinical Genetics and Genomics, Kitasato University Hospital, Kanagawa 252-0374, Japan.
9
Department of Neonatology, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan.
10
Department of Neonatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo 130-8575, Japan.
11
Intractable Disease Center, Saitama Medical University Hospital, Saitama 350-1298, Japan.

Abstract

Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.

KEYWORDS:

TRPV6; autosomal recessive; calcium; hyperparathyroidism; neonatal; placenta; skeletal; transient

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