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

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 Ca-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.

Post-mortem histology in transient receptor potential cation channel subfamily V member 6 (TRPV6) under-mineralising skeletal dysplasia suggests postnatal skeletal recovery: a case report

“…This leads to postnatal skeletal and biochemical abnormalities which progressively improve in the ex utero environment, as described in seven recent cases. 12,13 Skeletal findings improved postnatally in all cases, although in our case [12] the phenotype was extremely severe. In particular, the abnormally small rib cage led to life-threatening respiratory insufficiency.…”

“…While intraamniotic calcium infusions could theoretically prevent or correct bone abnormalities, improving thoracic growth and optimising future lung function, their risk profile of pregnancy loss means they are not a realistic approach. It has been proposed that small molecular chaperones, such as those used in cystic fibrosis, could be used antenatally to correct the conformation of TRPV6 variants, although this remains hypothetical at present [13].…”

“…Very recently in 2018, homozygous or compound heterozygous TRPV6 variants have been reported in seven infants with a skeletal disorder of antenatal-onset characterised by poor mineralisation [12,13]. All seven infants had biochemical abnormalities of secondary neonatal hyperparathyroidism which completely normalised over several weeks.…”

Maternal Transient Receptor Potential Vanilloid 6 (Trpv6) Is Involved In Offspring Bone Development

“…Interestingly, human infants with Trpv6 mutations present with a similar phenotype as our mice. Bone abnormalities are detected in utero and result in reduced mineralization and dysplasia of the fetal skeleton . The murine bone phenotype persists although the pups do not depend on placental Ca 2+ transfer after birth.…”

“…Bone abnormalities are detected in utero and result in reduced mineralization and dysplasia of the fetal skeleton. (35,36) The murine bone phenotype persists although the pups do not depend on placental Ca 2þ transfer after birth. TRPV6 expression has also been reported in mammary glands.…”