TY - JOUR
T1 - A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes
AU - Pulli, Kristiina
AU - Saarimäki-Vire, Jonna
AU - Ahonen, Pekka
AU - Liu, Xiaonan
AU - Ibrahim, Hazem
AU - Chandra, Vikash
AU - Santambrogio, Alice
AU - Wang, Yafei
AU - Vaaralahti, Kirsi
AU - Iivonen, Anna-Pauliina
AU - Känsäkoski, Johanna
AU - Tommiska, Johanna
AU - Kemkem, Yasmine
AU - Varjosalo, Markku
AU - Vuoristo, Sanna
AU - Andoniadou, Cynthia L.
AU - Otonkoski, Timo
AU - Raivio, Taneli
PY - 2024/5/22
Y1 - 2024/5/22
N2 - MAPK activating death domain (MADD) is a multifunctional protein regulating small GTPases RAB3 and RAB27, MAPK signaling, and cell survival. Polymorphisms in the MADD locus are associated with glycemic traits, but patients with biallelic variants in MADD manifest a complex syndrome affecting nervous, endocrine, exocrine, and hematological systems. We identified a homozygous splice site variant in MADD 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 MADD exon 30 (dex30). We observed reduced numbers of β cells, decreased insulin content, and increased proinsulin-to-insulin ratio in dex30 human embryonic stem cell-derived pancreatic islets. Concordantly, dex30 led to decreased insulin expression in human β cell line EndoC-βH1. Furthermore, dex30 resulted in decreased luteinizing hormone expression in mouse pituitary gonadotrope cell line LβT2 but did not affect ontogeny of stem cell-derived GnRH neurons. Protein-protein interactions of wild-type and dex30 MADD revealed changes affecting multiple signaling pathways, while the GDP/GTP exchange activity of dex30 MADD remained intact. Our results suggest MADD-specific processes regulate hormone expression in pancreatic β cells and pituitary gonadotropes.
AB - MAPK activating death domain (MADD) is a multifunctional protein regulating small GTPases RAB3 and RAB27, MAPK signaling, and cell survival. Polymorphisms in the MADD locus are associated with glycemic traits, but patients with biallelic variants in MADD manifest a complex syndrome affecting nervous, endocrine, exocrine, and hematological systems. We identified a homozygous splice site variant in MADD 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 MADD exon 30 (dex30). We observed reduced numbers of β cells, decreased insulin content, and increased proinsulin-to-insulin ratio in dex30 human embryonic stem cell-derived pancreatic islets. Concordantly, dex30 led to decreased insulin expression in human β cell line EndoC-βH1. Furthermore, dex30 resulted in decreased luteinizing hormone expression in mouse pituitary gonadotrope cell line LβT2 but did not affect ontogeny of stem cell-derived GnRH neurons. Protein-protein interactions of wild-type and dex30 MADD revealed changes affecting multiple signaling pathways, while the GDP/GTP exchange activity of dex30 MADD remained intact. Our results suggest MADD-specific processes regulate hormone expression in pancreatic β cells and pituitary gonadotropes.
KW - Beta cells
KW - Endocrinology
KW - Genetic diseases
KW - Neuroendocrine regulation
KW - Reproductive biology
KW - 3111 Biomedicine
KW - 1182 Biochemistry, cell and molecular biology
U2 - 10.1172/jci.insight.167598
DO - 10.1172/jci.insight.167598
M3 - Article
C2 - 38775154
AN - SCOPUS:85194024790
SN - 2379-3708
VL - 9
JO - JCI INSIGHT
JF - JCI INSIGHT
IS - 10
M1 - e167598
ER -