Journal Article

A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes

Vuoristo, Sanna, Ahonen, Pekka, Wang, Yafei, Otonkoski, Timo, Tommiska, Johanna, Raivio, Taneli, Saarimäki-Vire, Jonna, Liu, Xiaonan, Santambrogio, Alice, Iivonen, Anna-Pauliina, Varjosalo, Markku, Ibrahim, Hazem, Andoniadou, Cynthia L., Kemkem, Yasmine, Chandra, Vikash, Känsäkoski, Johanna, Vaaralahti, Kirsi, Pulli, Kristiina

2024

Overview

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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Age / Amino acids / Animals / Apoptosis / Beta cells / Cell Line / Cell survival / Child development / Clonal deletion / Congenital diseases / Diabetes mellitus / Embryo cells / Endocrine disorders / Endocrinology / Estrogens / Exons - genetics / Female / Gene deletion / Genotype & phenotype / Glucose / Gonadotrophs - metabolism / Gonadotropin-releasing hormone / Growth hormones / Hematology / Humans / Hyperglycemia / Hypogonadism / Hypogonadism - genetics / Hypogonadism - metabolism / Hypogonadism - pathology / Insulin / Insulin - metabolism / Insulin resistance / Insulin-like growth factors / Insulin-Secreting Cells - metabolism / Luteinizing hormone / Male / MAP kinase / Mice / Mutation / Ontogeny / Pancreas / Parents & parenting / Patients / Phenotypes / Phosphorylation / Pituitary / Pituitary (anterior) / Polymorphism / Protein interaction / Proteins / Puberty / rab3 GTP-Binding Proteins - genetics / rab3 GTP-Binding Proteins - metabolism / Reproductive biology / RNA Splice Sites - genetics / Siblings / Stem cells / Whole genome sequencing