Genetic and epigenetic states of the GNAS complex in pseudohypoparathyroidism type Ib using methylation-specific multiplex ligation-dependent probe amplification assay.

Abstract

CONTEXT:

Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder resulting from genetic and epigenetic aberrations in the GNAS complex. PHP-Ib, usually defined by renal resistance to parathyroid hormone, is due to a maternal loss of GNAS exon A/B methylation and leads to decreased expression of the stimulatory G protein α (Gsα) in specific tissues.

OBJECTIVE:

To clarify the usefulness of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), we evaluated genetic and epigenetic changes of the GNAS locus in Japanese PHP-Ib patients.

DESIGN:

Retrospective case series.

PATIENTS:

We studied 13 subjects with PHP-Ib (three families with eight affected members and one unaffected member and four sporadic cases).

MEASUREMENTS:

The methylation status of GNAS differentially methylated regions (DMRs) was evaluated using MS-MLPA. The main outcome measure was the presence of deletion mutations in the GNAS locus and STX16, which were assessed using MLPA.

RESULTS:

In all familial PHP-Ib cases, a ~3 kb deletion of STX16 and demethylation of the A/B domain were identified. In contrast, no deletion was detected throughout the entire GNAS locus region in the sporadic cases. Broad methylation abnormalities were observed in the GNAS DMRs.

CONCLUSIONS:

MS-MLPA allows for precise and rapid analysis of the methylation status in GNAS DMRs as well as the detection of microdeletion mutations in PHP-Ib. Results confirm the previous findings in this disorder and demonstrate that this method is valuable for the genetic evaluation and visualizing the methylation status. The MS-MLPA assay is a useful tool that may facilitate making the molecular diagnosis of PHP-Ib.

• Authors: Akiko Yuno, Takeshi Usui, Yuko Yambe, Kiichiro Higashi, Satoshi Ugi, Junji Shinoda, Yasuo Mashio, Akira Shimatsu
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 168 Issue 2 Pg. 169-75 (Feb 2013) ISSN: 1479-683X [Electronic] England
• PMID: 23132697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromogranins
• GNAS protein, human
• GTP-Binding Protein alpha Subunits, Gs

Topics

• Chromogranins
• DNA Methylation
• Epigenesis, Genetic
• Female
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Genomic Imprinting
• Humans
• Male
• Multiplex Polymerase Chain Reaction
• Pseudohypoparathyroidism (genetics)
• Retrospective Studies
• Sequence Deletion