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


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.
Department of Clinical Sciences and Community Health (F.M.E., E.P., P.B., P.B.-P., A.S., G.Ma.), Endocrinology and Diabetology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy; Department of Public Health and Pediatrics (L.d.S.), University of Turin, Regina Margherita Children's Hospital, 10126 Turin, Italy; and Department of Laboratory Medicine (B.P., G.Mi.), Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital, 33085 Pordenone, Italy.
Francesca M
FM
Elli
Luisa
L
de Sanctis
Erika
E
Peverelli
Paolo
P
Bordogna
Barbara
B
Pivetta
Gianmaria
G
Miolo
Paolo
P
Beck-Peccoz
Anna
A
Spada
Giovanna
G
Mantovani
D019175:DNA Methylation / Q000235:genetics*; D017353:Gene Deletion; D005799:Genes, Dominant; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D051438:Syntaxin 16 / Q000235:genetics*; D055815:Young Adult
C496118:STX16 protein, human; D051438:Syntaxin 16