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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3792-3796
Copyright © 1999 by The Endocrine Society

Original Studies

A Novel Mutation of the Signal Peptide of the Preproparathyroid Hormone Gene Associated with Autosomal Recessive Familial Isolated Hypoparathyroidism1

Thongkum Sunthornthepvarakul, Sunchai Churesigaew and Supunnee Ngowngarmratana

Department of Medicine, Rajavithi Hospital (T.S., S.N.), and the Department of Pediatrics, Queen Sirikit National Institute of Child Health (S.C.), Bangkok 10400, Thailand

Address all correspondence and requests for reprints to: Thongkum Sunthornthepvarakul, M.D., Rajavithi Hospital, Bangkok 10400, Thailand. E-mail: thongkum{at}rajavithi.go.th

We report a novel mutation of the signal peptide of the prepro-PTH gene associated with autosomal recessive familial isolated hypoparathyroidism. The proposita presented with neonatal hypocalcemic seizures. Serum calcium was 1.5 mmol/L (normal, 2.0–2.5); phosphate was 3.6 mmol/L (normal, 0.9–1.5). She was born to consanguineous parents. A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Genomic DNA from the proposita was sequenced all exons of the prepro-PTH gene. A replacement of thymine with a cytosine was found in the first nucleotide of position 23 in the 25-amino acid signal peptide. This results in the replacement of the normal Ser (TCG) with a Pro (CCG). Genotyping of family members was carried out by identification of a new MspI site created by the mutation. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance. As this mutation is at the -3 position in the signal peptide of the prepro-PTH gene, we hypothesized that the prepro-PTH mutant might not be cleaved by signal peptidase at the normal position, and it might be degraded in rough endoplasmic reticulum.




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