Intestinal failure or congenital diarrhoea

Gene: STX3

Green List (high evidence)

PMID:33974130 assembled a cohort of ten individuals from eight families with microvillus inclusion disease (MVID), which included follow up of five previously reported individuals and five new individuals. All of them had homozygous loss-of-function nonsense variants in STX3 gene. Eight of them presented with a novel syndrome consisting of MVID and early-onset severe retinal dystrophy (EOSRD). All six different variants identified in individuals with MVID and EOSRD are located in exons shared between the STX3A and the STX3B transcripts, while the single variant (p.Arg247Ter) present in other two individuals with MVID only is located in exon 9A and it spares STX3B transcript.

Functional studies showed that STX3B transcript is highly expressed in human retina and that the protein is enriched in the inner and outer segments of photoreceptors and in ribbon synapses of the human retina. The study also showed that the inactivation of Stx3 in murine rod photoreceptors leads to a progressive degeneration of photoreceptors, corroborating a recently published study that used a different Stx3 knockout mouse line.

In summary, biallelic variants affecting both STX3A and STX3B transcripts cause MVID and EOSRD, while variants affecting only STX3A transcript cause MVID.

This gene has been associated with both phenotypes in OMIM (MIMs #619445 & #619446), but not yet in Gene2Phenotype.

Created: 19 Sep 2024, 9:38 a.m. | Last Modified: 19 Sep 2024, 9:38 a.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Diarrhea 12, with microvillus atrophy, OMIM:619445; Retinal dystrophy and microvillus inclusion disease, OMIM:619446

Publications

• 33974130

This gene has been confirmed for this panel by the NHS Genomic Medicine Service and should be rated green.

Created: 8 Mar 2022, 11:44 a.m. | Last Modified: 8 Mar 2022, 11:44 a.m.

Panel Version: 1.48

Green List (high evidence)

Wiegerinck et al 2014 found homozygous truncating mutations in 2 consanguineous patients with MVID by exome sequencing. Western blot confirmed loss of protein expression in 1 case and mislocalisation of truncated protein in 2nd case. In vitro functional analysis showed statistically significant increase of both microvillus inclusions and basolateral microvilli and reduction of endogenous STX3 levels by overexpression of truncated, but not full-length, STX3 protein suggesting a dominant-negative effect.
Dhekne et al 2017: MYO5B, STX3, or STXBP2 encoded proteins all have roles in apical membrane trafficking in epithelial cells leading to suggestion that these three genes and their encoded proteins represent a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. They analyzed the subcellular distribution of syntaxin-3 and munc18-2 in enterocytes of intestinal biopsies from patients with MYO5B or STXBP2 mutations and found abnormal STX3 localisation. Authors say this provides compelling evidence that myosin Vb,syntaxin-3, and munc18-2 are functionally linked in human enterocytes, and likely comprise a common molecular pathway and disease mechanism that unifies a subgroup of congenital diarrheal disorders.
NOTE: PubMed: 25358429 identified homozygous missense STX3 mutation in a patient with autosomal recessive congenital cataract and intellectual disability phenotype without reported intestinal symptoms therefore milder mutations may be associated with alternate phenotype (similar to MYO5B missense mutations and cholestasis)

Created: 21 Jan 2019, 2:09 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microvillus inclusion disease; congenital diarrheal disorder

Publications

• 24726755
• 29266534

Green List (high evidence)

Comment when marking as ready: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 31 Jan 2019, 10:55 a.m.

Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: STX3; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 8 Jan 2019, 10:52 a.m.