Tobias, E. S. et al. (2024) SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis. Endocrine, (doi: 10.1007/s12020-024-03701-x) (PMID:38400880) (Early Online Publication)
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Abstract
Purpose: Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. Methods: Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. Results: By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. Conclusions: SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.
| Item Type: | Articles |
|---|---|
| Additional Information: | The next generation sequencing was facilitated by grants from the Wellcome Trust ISSF and Scottish Genomes Partnership. This Scottish Genomes Partnership is funded by the Chief Scientist Office of the Scottish Government Health Directorates [SGP/1] and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). AKLH is funded by an NES/CSO Clinical Lectureship. |
| Keywords: | endocrine, pituitary, DSD, exome, genome, SEC31A, COPII. |
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Hamilton, Dr Graham and Rios, Dr Francisco and McGowan, Ruth and Gazdagh, Dr Gabriella and Tobias, Professor Edward and Herzyk, Dr Pawel and De Lucca Camargo, Ms Livia and Diver, Miss Louise and Ahmed, Professor Syed Faisal and Williams, Miss Nicola and Montezano, Dr Augusto and Lucas-Herald, Dr Angela and Touyz, Professor Rhian |
| Authors: | Tobias, E. S., Lucas-Herald, A. K., Sagar, D., Montezano, A. C., Rios, F. J., De Lucca Camargo, L., Hamilton, G., Gazdagh, G., Diver, L. A., Williams, N., Herzyk, P., Touyz, R. M., Greenfield, A., McGowan, R., and Ahmed, S. F. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Endocrine |
| Publisher: | Springer |
| ISSN: | 1355-008X |
| ISSN (Online): | 1559-0100 |
| Published Online: | 24 February 2024 |
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