Background: Neonatal severe primary hyperparathyroidism (NSHPT, MIM 239200) is most often an isolated disorder that is due to biallelic inactivating mutations in the CASR, the gene encoding the calcium sensing receptor; NSHPT is inherited from parents with familial hypocalciuric hypercalcemia, each of whom has one mutated CASR allele. Objectives: To report clinical and genetic findings in a brother and sister with NSHPT due to a novel mutation in the CASR transmitted as an autosomal recessive trait and to examine the functional effect of the mutation. Subjects and methods: A brother and sister with marked hypercalcemia due to NSHPT were identified; the boy also had craniosynostosis requiring surgical repair. The genotyping of the CASR in both children and their parents who were eucalcemic and normophosphatemic was undertaken. In order to examine the significance of the variant CASR identified, the CASR variant was expressed in vitro and examined by three computer computational programs [PolyPhen2, MutationTaster, Sorting Intolerant From Tolerant (SIFT)] designed to evaluate the effect of a nucleotide variant on the structure and likely functional consequence upon the protein product. Results: A sequence variant in the CASR was identified [G>T point mutation at nucleotide c.2303 in exon 7 (c.2303G>T) resulting in the replacement of glycine by valine at codon 768 (p.Gly768Val)]. Two copies of this CASR variant were present in the genome of the siblings while a single copy of the CASR variant was present in both of the clinically and biochemically normal parents, a pattern of transmission consistent with autosomal recessive inheritance of NSHPT in this family. When expressed in HEK293 cells in vitro, the novel Gly768Val variant did not interfere with protein generation or migration to the cell membrane in vitro. The analysis of the functional effect of the Gly768Val CASR variant by the PolyPhen2, MutationTaster, and Sorting Intolerant From Tolerant computer programs revealed that this mutation was very likely to be deleterious. Conclusion: The NSHPT associated with biallelic Gly768Val mutations of the CASR in two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.
- calcium sensing receptor (CaSR)
- familial/hereditary hypocalciuric hypercalcemia
- neonatal hypercalcemia
- neonatal severe hyperparathyroidism
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Endocrinology, Diabetes and Metabolism