Stx16, short for syntaxin-16, is a gene whose role is intricately linked to the regulation of imprinting at the GNAS locus [1,3-10]. The GNAS locus is involved in the synthesis of the alpha-subunit of the stimulatory G protein (Gsα) and its splice variants, which are crucial for G protein-coupled receptor (GPCR) signaling pathways [1].

Mutations or deletions in Stx16, especially maternally inherited ones, are a common cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B) [1,3-7,9,10]. For instance, a 3-kb STX16 deletion is frequently observed and leads to loss of methylation at the GNAS exon A/B, reducing Gsα expression and resulting in parathyroid hormone (PTH)-resistant hypocalcemia and hyperphosphatemia [3,4,5,6,7]. In a 39-year-old male patient with PHP1B, a half-reduced copy number of STX16 exon 5-7 was detected along with loss of methylation at GNAS exon A/B [2]. Also, children inheriting a STX16 deletion maternally show an increase in PTH levels by 2 years of age, with the development of overt hypocalcemia around 5 years of age [3]. There is a preferential maternal transmission of STX16-GNAS mutations, which may be related to oocyte maturation abnormalities [5].

In conclusion, Stx16 plays a vital role in the regulation of GNAS locus imprinting. Its loss-of-function, often through deletions, is closely associated with AD-PHP1B. Understanding Stx16's function through these disease-related studies provides insights into the molecular mechanisms underlying pseudohypoparathyroidism and can potentially guide genetic testing and counseling for this disorder.

References:

1. Jüppner, Harald. . Molecular Definition of Pseudohypoparathyroidism Variants. In The Journal of clinical endocrinology and metabolism, 106, 1541-1552. doi:10.1210/clinem/dgab060. https://pubmed.ncbi.nlm.nih.gov/33529330/

2. Chen, Li, Yang, Chuanbin, Zhang, Xiaoxiao, Yue, Xiaofang, Yang, Jiajun. 2024. STX16 exon 5-7 deletion in a patient with pseudohypoparathyroidism type 1B. In Journal of pediatric endocrinology & metabolism : JPEM, 37, 734-740. doi:10.1515/jpem-2023-0562. https://pubmed.ncbi.nlm.nih.gov/39026465/

3. Kiuchi, Zentaro, Reyes, Monica, Hanna, Patrick, Tebben, Peter, Jüppner, Harald. . Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions. In The Journal of clinical endocrinology and metabolism, 107, e681-e687. doi:10.1210/clinem/dgab660. https://pubmed.ncbi.nlm.nih.gov/34477200/

4. Kostopoulos, Georgios, Tzikos, Georgios, Sortsis, Alexandros, Toulis, Konstantinos. 2022. Autosomal dominant pseudohypoparathyroidism type 1b due to STX16 deletion: a case presentation and literature review. In Minerva endocrinology, 49, 217-225. doi:10.23736/S2724-6507.20.03233-2. https://pubmed.ncbi.nlm.nih.gov/35119251/

5. Kiuchi, Zentaro, Reyes, Monica, Jüppner, Harald. 2020. Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion. In Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 36, 696-703. doi:10.1002/jbmr.4221. https://pubmed.ncbi.nlm.nih.gov/33247854/

6. Yang, Yi, Chu, Xueying, Nie, Min, Xing, Xiaoping, Wang, Ou. 2020. A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B. In Endocrine, 69, 212-219. doi:10.1007/s12020-020-02304-6. https://pubmed.ncbi.nlm.nih.gov/32337648/

7. Turan, Serap, Ignatius, Jaakko, Moilanen, Jukka S, Bastepe, Murat, Jüppner, Harald. 2012. De novo STX16 deletions: an infrequent cause of pseudohypoparathyroidism type Ib that should be excluded in sporadic cases. In The Journal of clinical endocrinology and metabolism, 97, E2314-9. doi:10.1210/jc.2012-2920. https://pubmed.ncbi.nlm.nih.gov/23087324/