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

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

doi:10.1172/jci.insight.167598

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

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

Centre for Craniofacial & Regenerative Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	e167598
Journal	JCI Insight
Volume	9
Issue number	10
DOIs	https://doi.org/10.1172/jci.insight.167598
Publication status	Published - 22 May 2024

Keywords

Insulin-Secreting Cells/metabolism
Humans
Animals
Mice
Male
Gonadotrophs/metabolism
Female
RNA Splice Sites/genetics
Cell Line
Insulin/metabolism
Siblings
Exons/genetics
rab3 GTP-Binding Proteins/metabolism
Hypogonadism/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/jci.insight.167598

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Pulli, K., Saarimäki-Vire, J., Ahonen, P., Liu, X., Ibrahim, H., Chandra, V., Santambrogio, A., Wang, Y., Vaaralahti, K., Iivonen, A.-P., Känsäkoski, J., Tommiska, J., Kemkem, Y., Varjosalo, M., Vuoristo, S., Andoniadou, C. L., Otonkoski, T., & Raivio, T. (2024). A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes. JCI Insight, 9(10), Article e167598. https://doi.org/10.1172/jci.insight.167598

@article{8f8d1e94cdc843b38bd815bffe6c0db9,

title = "A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes",

abstract = "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.",

keywords = "Insulin-Secreting Cells/metabolism, Humans, Animals, Mice, Male, Gonadotrophs/metabolism, Female, RNA Splice Sites/genetics, Cell Line, Insulin/metabolism, Siblings, Exons/genetics, rab3 GTP-Binding Proteins/metabolism, Hypogonadism/genetics",

author = "Kristiina Pulli and Jonna Saarim{\"a}ki-Vire and Pekka Ahonen and Xiaonan Liu and Hazem Ibrahim and Vikash Chandra and Alice Santambrogio and Yafei Wang and Kirsi Vaaralahti and Anna-Pauliina Iivonen and Johanna K{\"a}ns{\"a}koski and Johanna Tommiska and Yasmine Kemkem and Markku Varjosalo and Sanna Vuoristo and Andoniadou, {Cynthia L} and Timo Otonkoski and Taneli Raivio",

note = "Publisher Copyright: {\textcopyright} 2024, Pulli et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2024",

month = may,

day = "22",

doi = "10.1172/jci.insight.167598",

language = "English",

volume = "9",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "10",

}

Pulli, K, Saarimäki-Vire, J, Ahonen, P, Liu, X, Ibrahim, H, Chandra, V, Santambrogio, A, Wang, Y, Vaaralahti, K, Iivonen, A-P, Känsäkoski, J, Tommiska, J, Kemkem, Y, Varjosalo, M, Vuoristo, S, Andoniadou, CL, Otonkoski, T & Raivio, T 2024, 'A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes', JCI Insight, vol. 9, no. 10, e167598. https://doi.org/10.1172/jci.insight.167598

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 - Insulin-Secreting Cells/metabolism

KW - Humans

KW - Animals

KW - Mice

KW - Male

KW - Gonadotrophs/metabolism

KW - Female

KW - RNA Splice Sites/genetics

KW - Cell Line

KW - Insulin/metabolism

KW - Siblings

KW - Exons/genetics

KW - rab3 GTP-Binding Proteins/metabolism

KW - Hypogonadism/genetics

UR - http://www.scopus.com/inward/record.url?scp=85194024790&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.167598

DO - 10.1172/jci.insight.167598

M3 - Article

C2 - 38775154

SN - 2379-3708

VL - 9

JO - JCI Insight

JF - JCI Insight

IS - 10

M1 - e167598

ER -

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

Abstract

Keywords

UN SDGs

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