Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR.

Abstract

CONTEXT:

Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods.

OBJECTIVE:

We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underlying primary genetic defect.

PATIENT AND METHODS:

A PHP-Ib patient (hypocalcaemia, hyperphosphataemia, raised serum PTH levels, no vitamin D deficiency) and his unaffected relatives were investigated by methylation specific-multiplex ligand-dependent probe amplification to search for novel pathogenetic defects affecting the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 and STX16 loci.

RESULTS:

We report the clinical, biochemical, and molecular analysis of an AD-PHP-Ib patient with a novel STX16 deletion overlapping with previously identified STX16 deletions but that, unlike these genetic defects associated with AD-PHP-Ib, goes unnoticed with commonly used first-level diagnostic techniques.

CONCLUSIONS:

Our work highlights the importance of performing accurate investigations in PHP-Ib patients with methylation defects to allow precise genetic counseling because, in case of deletions, the segregation ratio is about 50% and the disease phenotype is transmitted in an autosomal dominant fashion via the mother.

• Authors: Francesca M Elli, Luisa de Sanctis, Erika Peverelli, Paolo Bordogna, Barbara Pivetta, Gianmaria Miolo, Paolo Beck-Peccoz, Anna Spada, Giovanna Mantovani
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 99 Issue 4 Pg. E724-8 (Apr 2014) ISSN: 1945-7197 [Electronic] United States
• PMID: 24438374 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STX16 protein, human
• Syntaxin 16

Topics

• DNA Methylation (genetics)
• Gene Deletion
• Genes, Dominant
• Genomic Imprinting (genetics)
• Humans
• Male
• Pedigree
• Pseudohypoparathyroidism (genetics)
• Syntaxin 16 (genetics)
• Young Adult