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Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects
- Source :
- Human Genetics, 140(8), 1143-1156. Springer-Verlag, Human Genetics
- Publication Year :
- 2021
-
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.
- Subjects :
- chemistry.chemical_compound
Mice
0302 clinical medicine
Mucolipidoses
Enteropathy
Intestinal Mucosa
Genetics (clinical)
Exome sequencing
Original Investigation
Genetics
Aged, 80 and over
Mice, Knockout
0303 health sciences
Microvilli
Qa-SNARE Proteins
Homozygote
Eye Diseases, Hereditary
Disease gene identification
Phenotype
medicine.anatomical_structure
Knockout mouse
Retinal Cone Photoreceptor Cells
Female
Autopsy
Co-Repressor Proteins
Biology
Polymorphism, Single Nucleotide
03 medical and health sciences
Malabsorption Syndromes
SDG 3 - Good Health and Well-being
Retinal Dystrophies
Exome Sequencing
medicine
Animals
Humans
Sensory Rhodopsins
RNA, Messenger
Outer nuclear layer
030304 developmental biology
Aged
Retinal
medicine.disease
Human genetics
Alcohol Oxidoreductases
chemistry
Gene Expression Regulation
sense organs
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 03406717
- Volume :
- 140
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Human Genetics
- Accession number :
- edsair.doi.dedup.....61dc5a4535447fa78f5680c9aee003e4