Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

Hum Genet. 2021 Aug;140(8):1143-1156. doi: 10.1007/s00439-021-02284-1.

Andreas R Janecke ¹ ², Xiaoqin Liu ³, Rüdiger Adam ⁴, Sumanth Punuru ³, Arne Viestenz ⁵, Valeria Strauß ⁶, Martin Laass ⁷, Elizabeth Sanchez ⁸, Roberto Adachi ⁸, Martha P Schatz ⁹, Ujwala S Saboo ⁹, Naveen Mittal ¹⁰, Klaus Rohrschneider ¹¹, Johanna Escher ¹², Anuradha Ganesh ¹³, Sana Al Zuhaibi ¹³, Fathiya Al Murshedi ¹⁴, Badr AlSaleem ¹⁵, Majid Alfadhel ¹⁶, Siham Al Sinani ¹⁷, Fowzan S Alkuraya ¹⁸, Lukas A Huber ¹⁹, Thomas Müller ²⁰, Ruth Heidelberger ^# ²¹, Roger Janz ^# ³ ²²

Affiliations

1 Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. [email protected].
2 Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria. [email protected].
3 Department of Neurobiology and Anatomy, MSB 7.046, McGovern Medical School at the University of Texas HSC (UTHealth), 6431 Fannin Street, Houston, TX, 77030, USA.
4 University Children's Hospital, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
5 Department of Ophthalmology, University Medical Center Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
6 Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Halle, Halle, Germany.
7 Klinik und Poliklinik f. Kinder- u. Jugendmedizin, University of Dresden, Dresden, Germany.
8 Department of Pulmonary Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9 Department of Ophthalmology, University of Texas Health Science Center, San Antonio, TX, USA.
10 Department of Department of Pediatrics, Division of Pediatric Gastroenterology, University of Texas Health Science Center, San Antonio, TX, USA.
11 Augenklinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
12 Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
13 Department of Ophthalmology, Sultan Qaboos University Hospital, Muscat, Oman.
14 Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
15 King Fahad Medical City, Children's Specialized Hospital, Riyadh, Saudi Arabia.
16 Genetics Division and Medical Genomic Research Lab, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.
17 Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.
18 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
19 Division of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria.
20 Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
21 Department of Neurobiology and Anatomy, MSB 7.046, McGovern Medical School at the University of Texas HSC (UTHealth), 6431 Fannin Street, Houston, TX, 77030, USA. [email protected].
22 Center for Scientific Review, National Institutes of Health, Bethesda, MD, USA.
# Contributed equally.

PMID: 33974130 DOI: 10.1007/s00439-021-02284-1

Abstract

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

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