PT  - JOURNAL ARTICLE
AU  - Rie Asada Kitamura
AU  - Kristina G. Maxwell
AU  - Wenjuan Ye
AU  - Kelly Kries
AU  - Cris M Brown
AU  - Punn Augsornworawat
AU  - Yoel Hirsch
AU  - Martin M Johansson
AU  - Tzvi Weiden
AU  - Joseph Ekstein
AU  - Joshua Cohen
AU  - Justin Klee
AU  - Kent Leslie
AU  - Anton Simeonov
AU  - Mark J. Henderson
AU  - Jeffrey R. Millman
AU  - Fumihiko Urano
TI  - Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome
AID  - 10.1101/2021.11.07.467657
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.07.467657
4099  - http://biorxiv.org/content/early/2021/11/08/2021.11.07.467657.short
4100  - http://biorxiv.org/content/early/2021/11/08/2021.11.07.467657.full
AB  - Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.One sentence summary Development of personalized therapy for Wolfram syndrome using genetics and iPSC model.Competing Interest StatementF. Urano is an inventor of three patents related to the treatment of Wolfram syndrome, US 9,891,231 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574 and US 10,695,324 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. F. Urano is a Founder and President of CURE4WOLFRAM, INC.