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

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.

• Authors: Andreas R Janecke, Xiaoqin Liu, Rüdiger Adam, Sumanth Punuru, Arne Viestenz, Valeria Strauß, Martin Laass, Elizabeth Sanchez, Roberto Adachi, Martha P Schatz, Ujwala S Saboo, Naveen Mittal, Klaus Rohrschneider, Johanna Escher, Anuradha Ganesh, Sana Al Zuhaibi, Fathiya Al Murshedi, Badr AlSaleem, Majid Alfadhel, Siham Al Sinani, Fowzan S Alkuraya, Lukas A Huber, Thomas Müller, Ruth Heidelberger, Roger Janz
• Journal: Human genetics (Hum Genet) Vol. 140 Issue 8 Pg. 1143-1156 (Aug 2021) ISSN: 1432-1203 [Electronic] Germany
• PMID: 33974130 (Publication Type: Journal Article)

Chemical References

• Co-Repressor Proteins
• Qa-SNARE Proteins
• RNA, Messenger
• Sensory Rhodopsins
• Alcohol Oxidoreductases
• CTBP2 protein, human

Topics

• Aged
• Aged, 80 and over
• Alcohol Oxidoreductases (genetics, metabolism)
• Animals
• Autopsy
• Co-Repressor Proteins (genetics, metabolism)
• Eye Diseases, Hereditary (genetics, metabolism, pathology)
• Female
• Gene Expression Regulation
• Homozygote
• Humans
• Intestinal Mucosa (metabolism, pathology)
• Malabsorption Syndromes (genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• Microvilli (genetics, metabolism, pathology)
• Mucolipidoses (genetics, metabolism, pathology)
• Phenotype
• Polymorphism, Single Nucleotide
• Qa-SNARE Proteins (deficiency, genetics)
• RNA, Messenger (genetics, metabolism)
• Retinal Cone Photoreceptor Cells (metabolism, pathology)
• Retinal Dystrophies (genetics, metabolism, pathology)
• Sensory Rhodopsins (genetics, metabolism)
• Exome Sequencing