THE CLINICAL SPECTRUM AND GENETIC CHARACTERISTICS OF MONOGENIC DIABETES IN THE STATE OF QATAR: A SPOTLIGHT ON USING PLURIPOTENT STEM CELLS TO UNDERSTAND PANCREATIC BETA CELL DEVELOPMENT AND PATHOPHYSIOLOGY

Abstract

Monogenic diabetes (MD), including permanent neonatal diabetes mellitus (PNDM) and maturity onset diabetes of the young (MODY) are rare conditions caused by mutations in specific genes. Most of those genes are known for their expression at early and/or late stages of pancreatic beta- cell development. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of MD among the Qatari population. The cellular basis of these mutations remains largely unknown due to lack of the models that can recapitulate the genotype-phenotype correlations. The aim of the current study was to identify patients with MD diagnosed between 2001 and 2016 and to use human pluripotent stem cell (hPSC) technology to generate early stages of pancreatic beta cell development as a unique cellular model to recapitulate the disease. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the monogenic diabetes cohort. Our results showed that the majority of cases of PNDM in Qatar were rare familial autosomal-recessive syndromes. Seven different mutations were identified with PTF1A deletion being the most common in the PNDM cohort. Novel mutations in the INS and HNF1B genes were detected. Since most of the mutations identified in this study are expressed at early stages of pancreatic beta-cell development, we aimed to establish a differentiation protocol using hPSCs to generate those stages. We have differentiated hPSCs into definitive endoderm, primitive gut tube, posterior foregut, and pancreatic progenitors with higher efficiency compared to the previously established protocols. hPSC-derived progenitors expressed high levels of PDX1 and NKX6.1, the key transcription factors for pancreatic beta cells. In conclusion, here we have provided the first comprehensive study to identify MD, among the Qatari population and generated early stages of pancreatic beta cell development.

Date of Award	2019
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences