An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism

✍ Scribed by Dsouza-Li, Lilia (author);Canaff, Lucie (author);Janicic, Natasa (author);Cole, David E.C. (author);Hendy, Geoffrey N. (author)

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 595 KB
• Volume: 18
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.1212

✦ Synopsis

We studied family members of a large kindred expressing both familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) and found, by PCR amplification of the extracellular calcium-sensing receptor (CASR) gene exons and flanking intronic sequences, that FHH individuals were heterozygous for a g to t substitution in the last nucleotide of intron 2 (IVS2-1G>T). Defects in messenger RNA splicing were investigated by illegitimate transcription of the CASR gene in lymphoblastoid cells from an FHH affected individual, as well as by transfection of a CASR minigene harboring this mutation into HEK293 cells. The mutation resulted predominantly in exon III skipping causing a shift in exon IV reading frame and introduction of a premature stop codon leading to a predicted truncated protein of 153 amino acids. Interestingly, it was noted that exon III splicing is not 100% efficient in parathyroid, thyroid, and kidney; an exon III-deleted transcript is produced approximately 15% of the time. This is the first description of a splice site mutation in the CASR gene and provides an explanation of the clinical phenotype of the patients.