STX16 – Pseudohypoparathyroidism Type 1B

STX16 encodes a SNARE protein whose maternal deletions disrupt imprinting control at the GNAS locus, causing Pseudohypoparathyroidism Type 1B. Affected individuals present with hypocalcemia (HP:0002901), hyperphosphatemia (HP:0002905), tetany (HP:0001281), and seizures (HP:0001250), reflecting end-organ resistance to parathyroid hormone without Albright hereditary osteodystrophy features.

Genetic studies have identified maternal STX16 deletions in multiple unrelated kindreds, including a 3-kb deletion of exons 4–6 in seven families ([PMID:34157100]), a 492.3 kb deletion encompassing the entire gene in one case ([PMID:38233937]), and small deletions upstream of GNAS in two individuals ascertained for early-onset obesity ([PMID:28453643]). Paternal uniparental disomy of chromosome 20q has also been reported in two sporadic patients with PHP1B ([PMID:23144470]).

These variants consistently demonstrate an autosomal dominant pattern with maternal inheritance, with at least 12 unrelated probands reported ([PMID:34157100]), and segregation of deletions with the disease phenotype across multiple families.

Functional assays using methylation-specific MLPA and quantitative pyrosequencing have shown loss of methylation at the GNAS exon A/B differentially methylated region in all affected individuals harboring STX16 deletions ([PMID:26479409]), with concordant imprinting defects observed in patient-derived lymphoblastoid cell lines.

No studies have refuted the association, and no conflicting evidence has emerged. The concordance of clinical, genetic, and epigenetic data establishes a clear mechanism whereby STX16 haploinsufficiency abrogates imprinting control at GNAS, leading to PTH resistance.

In summary, maternal STX16 deletions are a strong and clinically actionable cause of Pseudohypoparathyroidism Type 1B. Key Take-home: Testing for STX16 deletions alongside GNAS methylation analysis is essential for accurate diagnosis and management of patients with unexplained hypocalcemia and hyperphosphatemia.

References

• Nephrology (Carlton, Vic.) • 2024 • Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B. PMID:38233937
• The Journal of Clinical Endocrinology and Metabolism • 2013 • Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. PMID:23144470
• The Journal of Clinical Endocrinology and Metabolism • 2017 • Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes. PMID:28453643
• The Journal of Clinical Endocrinology and Metabolism • 2021 • High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects. PMID:34157100
• Journal of Bone and Mineral Research • 2016 • Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion. PMID:26479409
• Journal of Cellular Physiology • 2021 • SNAREs and developmental disorders. PMID:32959907

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