Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
Autosomal dominant hypocalcemia, caused by activating mutations of the calcium-sensing receptor (CASR) gene, is characterized by hypocalcemia with an inappropriately low concentration of parathyroid hormone (PTH). In this report, we describe the identification of a novel missense mutation in the CASR gene, in a boy with autosomal dominant hypocalcemia. Polymerase chain reaction (PCR)-single strand and DNA sequencing revealed a heterozygous mutation in CASR gene that causes a leucine substitution for serine at codon 123 (p.Leu123Ser). This mutation was absent in DNA from 50 control patients. In silico studies suggest that the identified variant was likely pathogenic. Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected. Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later, namely, hand tremor and rigidity at the age of 7 and 18 years, respectively. Laboratory analysis revealed hypocalcemia, hyperphosphatemia, and low-serum PTH with hypomagnesemia and mild hypercalciuria. After 2 years of treatment with calcium supplements and calcitriol, some brief periods of clinical improvement were reported; as well as an absence of nephrocalcinosis.
Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal.
Joana
J
Regala
Molecular Pathobiology Research Centre, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal; Chronic Diseases Research Center, NOVA Medical School, NOVA University of Lisbon, Lisbon, Portugal.
Branca
B
Cavaco
Molecular Pathobiology Research Centre, Portuguese Institute of Oncology Francisco Gentil, Lisbon, Portugal; Chronic Diseases Research Center, NOVA Medical School, NOVA University of Lisbon, Lisbon, Portugal.
Rita
R
Domingues
Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal.
Catarina
C
Limbert
Pediatric Endocrinology Unit, Dona Estefânia Pediatric Hospital, Hospital Centre of Central Lisbon, Lisbon, Portugal.
Lurdes
L
Lopes
autosomal dominant hypocalcemia; calcium-sensing receptor; missense mutation; mosaicism