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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620831
Title:
TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton.
Authors:
Burren, C. P.; Caswell, R.; Castle, B.; Welch, C. R.; Hilliard, T. N.; Smithson, S. F.; Ellard, Sian ( 0000-0002-7620-5526 )
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. p.(Gly660Arg) generates a large side chain protruding from the C-terminal hook into the interface with the adjacent TRPV6 subunit. In silico protein modeling suggests steric clashes between interface residues, decreased C-terminal hook, and TRPV6 tetramer stability. The p.(Gly660Arg) variant is predicted to result in profound loss of TRPV6 activity. This first case of a novel dysplasia features severe but improving perinatal abnormalities. The TRPV6 compound heterozygous variants appear likely to interfere with fetoplacental calcium transfer crucial for in utero skeletal development. Astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs exome sequencing interpretation.
Citation:
TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton. 2018, 176 (9):1950-1955 Am. J. Med. Genet. A
Publisher:
Wiley
Journal:
American journal of medical genetics. Part A
Issue Date:
Sep-2018
URI:
http://hdl.handle.net/11287/620831
DOI:
10.1002/ajmg.a.40484
PubMed ID:
30144375
Additional Links:
https://doi.org/10.1002/ajmg.a.40484
Type:
Journal Article
Language:
en
ISSN:
1552-4833
Appears in Collections:
Molecular Genetics; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorBurren, C. P.en
dc.contributor.authorCaswell, R.en
dc.contributor.authorCastle, B.en
dc.contributor.authorWelch, C. R.en
dc.contributor.authorHilliard, T. N.en
dc.contributor.authorSmithson, S. F.en
dc.contributor.authorEllard, Sianen
dc.date.accessioned2018-10-02T13:09:03Z-
dc.date.available2018-10-02T13:09:03Z-
dc.date.issued2018-09-
dc.identifier.citationTRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton. 2018, 176 (9):1950-1955 Am. J. Med. Genet. Aen
dc.identifier.issn1552-4833-
dc.identifier.pmid30144375-
dc.identifier.doi10.1002/ajmg.a.40484-
dc.identifier.urihttp://hdl.handle.net/11287/620831-
dc.description.abstractTransient 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. p.(Gly660Arg) generates a large side chain protruding from the C-terminal hook into the interface with the adjacent TRPV6 subunit. In silico protein modeling suggests steric clashes between interface residues, decreased C-terminal hook, and TRPV6 tetramer stability. The p.(Gly660Arg) variant is predicted to result in profound loss of TRPV6 activity. This first case of a novel dysplasia features severe but improving perinatal abnormalities. The TRPV6 compound heterozygous variants appear likely to interfere with fetoplacental calcium transfer crucial for in utero skeletal development. Astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs exome sequencing interpretation.en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttps://doi.org/10.1002/ajmg.a.40484en
dc.rightsArchived with thanks to American journal of medical genetics. Part Aen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleTRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of medical genetics. Part Aen
dc.type.versionPublisheden

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.