SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis.

Autor: Tobias ES; West of Scotland Centre for Genomic Medicine, Laboratory Medicine Building, Queen Elizabeth University Hospital, Govan Road, Glasgow, G51 4TF, UK. edward.tobias@glasgow.ac.uk.; Academic Unit of Medical Genetics and Clinical Pathology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK. edward.tobias@glasgow.ac.uk., Lucas-Herald AK; Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children, 1345 Govan Road, Glasgow, G51 4TF, UK., Sagar D; MRC Mammalian Genetics Unit, Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK., Montezano AC; Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK.; Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada., Rios FJ; Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK., De Lucca Camargo L; Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK.; Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada., Hamilton G; Glasgow Polyomics, College of Medical Veterinary and Life Sciences, Garscube Estate, Switchback Rd, Glasgow, G61 1BD, UK., Gazdagh G; West of Scotland Centre for Genomic Medicine, Laboratory Medicine Building, Queen Elizabeth University Hospital, Govan Road, Glasgow, G51 4TF, UK.; Academic Unit of Medical Genetics and Clinical Pathology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK., Diver LA; West of Scotland Centre for Genomic Medicine, Laboratory Medicine Building, Queen Elizabeth University Hospital, Govan Road, Glasgow, G51 4TF, UK., Williams N; West of Scotland Centre for Genomic Medicine, Laboratory Medicine Building, Queen Elizabeth University Hospital, Govan Road, Glasgow, G51 4TF, UK., Herzyk P; Glasgow Polyomics, College of Medical Veterinary and Life Sciences, Garscube Estate, Switchback Rd, Glasgow, G61 1BD, UK.; Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK., Touyz RM; Institute of Cardiovascular and Medical Sciences, British Heart Foundation Centre for Research Excellence, University of Glasgow, 126 University Avenue, Glasgow, G12 8TA, UK.; Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada., Greenfield A; MRC Mammalian Genetics Unit, Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK.; Nuffield Department of Women's & Reproductive Health, Institute of Reproductive Sciences, University of Oxford, Oxford, UK., McGowan R; West of Scotland Centre for Genomic Medicine, Laboratory Medicine Building, Queen Elizabeth University Hospital, Govan Road, Glasgow, G51 4TF, UK.; Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children, 1345 Govan Road, Glasgow, G51 4TF, UK., Ahmed SF; Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children, 1345 Govan Road, Glasgow, G51 4TF, UK.
Jazyk: angličtina
Zdroj: Endocrine [Endocrine] 2024 May; Vol. 84 (2), pp. 345-349. Date of Electronic Publication: 2024 Feb 24.
DOI: 10.1007/s12020-024-03701-x
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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