SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis

• Published in: Endocrine 2024-05, Vol.84 (2), p.345-349
• Main Authors: Tobias, Edward S., Lucas-Herald, Angela K., Sagar, Danielle, Montezano, Augusto C., Rios, Francisco J., De Lucca Camargo, Livia, Hamilton, Graham, Gazdagh, Gabriella, Diver, Louise A., Williams, Nicola, Herzyk, Pawel, Touyz, Rhian M., Greenfield, Andy, McGowan, Ruth, Ahmed, S. Faisal
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Brief Report; Child; Child, Preschool; Children; Coat protein; CRISPR; Diabetes; DNA sequencing; Endocrinology; Endoplasmic reticulum; Families & family life; Female; Gene expression; Genes; Golgi apparatus; Gonadal dysgenesis; Gonadal Dysgenesis - genetics; Humanities and Social Sciences; Humans; Hypopituitarism - genetics; Hypopituitarism - metabolism; Internal Medicine; Lethality; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; multidisciplinary; Pedigree; Phenotyping; Pituitary; Pituitary hormones; Pituitary Hormones - deficiency; Pituitary Hormones - genetics; Protein transport; Science; Vesicular Transport Proteins - genetics
• ISSN: 1559-0100; 1355-008X; 1559-0100
• DOI: 10.1007/s12020-024-03701-x

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.