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Polymorphisms in the\n                    <jats:italic>MADD<\/jats:italic>\n                    locus are associated with glycemic traits, but patients with biallelic variants in\n                    <jats:italic>MADD<\/jats:italic>\n                    manifest a complex syndrome affecting nervous, endocrine, exocrine, and hematological systems. We identified a homozygous splice site variant in\n                    <jats:italic>MADD<\/jats:italic>\n                    in 2 siblings with developmental delay, diabetes, congenital hypogonadotropic hypogonadism, and growth hormone deficiency. This variant led to skipping of exon 30 and in-frame deletion of 36 amino acids. To elucidate how this mutation causes pleiotropic endocrine phenotypes, we generated relevant cellular models with deletion of\n                    <jats:italic>MADD<\/jats:italic>\n                    exon 30 (\n                    <jats:italic>dex30<\/jats:italic>\n                    ). We observed reduced numbers of \u03b2 cells, decreased insulin content, and increased proinsulin-to-insulin ratio in\n                    <jats:italic>dex30<\/jats:italic>\n                    human embryonic stem cell\u2013derived pancreatic islets. Concordantly,\n                    <jats:italic>dex30<\/jats:italic>\n                    led to decreased insulin expression in human \u03b2 cell line EndoC-\u03b2H1. Furthermore,\n                    <jats:italic>dex30<\/jats:italic>\n                    resulted in decreased luteinizing hormone expression in mouse pituitary gonadotrope cell line L\u03b2T2 but did not affect ontogeny of stem cell\u2013derived GnRH neurons. Protein-protein interactions of wild-type and\n                    <jats:italic>dex30<\/jats:italic>\n                    <jats:italic>MADD<\/jats:italic>\n                    revealed changes affecting multiple signaling pathways, while the GDP\/GTP exchange activity of\n                    <jats:italic>dex30<\/jats:italic>\n                    <jats:italic>MADD<\/jats:italic>\n                    remained intact. Our results suggest\n                    <jats:italic>MADD<\/jats:italic>\n                    -specific processes regulate hormone expression in pancreatic \u03b2 cells and pituitary gonadotropes.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.167598","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T14:00:31Z","timestamp":1716300031000},"source":"Crossref","is-referenced-by-count":4,"title":["A splice site variant in MADD affects hormone expression in pancreatic \u03b2 cells and pituitary gonadotropes"],"prefix":"10.1172","volume":"9","author":[{"given":"Kristiina","family":"Pulli","sequence":"first","affiliation":[{"name":"Stem Cells and Metabolism Research Program (STEMM), Research Programs Unit, Faculty of Medicine, 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