TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton

American Journal of Medical Genetics. Part a
Christine P BurrenSian Ellard

Abstract

Transient receptor potential vanilloid 6 (TRPV6) functions in tetramer form for calcium transport. Until now, TRPV6 has not been linked with skeletal development disorders. An infant with antenatal onset thoracic insufficiency required significant ventilatory support. Skeletal survey showed generalized marked undermineralization, hypoplastic fractured ribs, metaphyseal fractures, and extensive periosteal reaction along femoral, tibial, and humeral diaphyses. Parathyroid hormone (PTH) elevation (53.4-101 pmol/L) initially suggested PTH signaling disorders. Progressively, biochemical normalization with radiological mineralization suggested recovery from in utero pathophysiology. Genomic testing was undertaken and in silico protein modeling of variants. No abnormalities in antenatal CGH array or UPD14 testing. Postnatal molecular genetic analysis found no causative variants in CASR, GNA11, APS21, or a 336 gene skeletal dysplasia panel investigated by whole exome sequencing. Trio exome analysis identified compound heterozygous TRPV6 likely pathogenic variants: novel maternally inherited missense variant, c.1978G > C p.(Gly660Arg), and paternally inherited nonsense variant, c.1528C > T p.(Arg510Ter), confirming recessive inheritance...Continue Reading

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Citations

Feb 21, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Claudia Fecher-TrostPetra Weissgerber
Feb 20, 2020·The Journal of Physiology·Maria V YelshanskayaAlexander I Sobolevsky
Apr 2, 2020·Protein Science : a Publication of the Protein Society·Mark K van GoorJenny van der Wijst
Aug 12, 2020·Experimental and Clinical Transplantation : Official Journal of the Middle East Society for Organ Transplantation·Mani RamziHourvash Haghighinejad
Jul 11, 2020·The Journal of Physiological Sciences : JPS·Yoshiro SuzukiMakoto Tominaga
Mar 2, 2019·Journal of the Endocrine Society·Sumie YamashitaDaisuke Hata
Nov 29, 2020·Science Advances·Rajesh BhardwajAlexander I Sobolevsky
Aug 10, 2019·Cellular and Molecular Gastroenterology and Hepatology·Megan R BeggsR Todd Alexander
Feb 22, 2021·Biochimica Et Biophysica Acta. General Subjects·Verena NettUlrich Wissenbach
May 9, 2021·Annals of Anatomy = Anatomischer Anzeiger : Official Organ of the Anatomische Gesellschaft·Karin WolskeUlrich Wissenbach
Nov 3, 2021·Nature Communications·Arthur NeubergerAlexander I Sobolevsky

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Methods Mentioned

BETA
exome sequencing
cesarean section

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