STX3 – Microvillus Inclusion Disease

This summary provides an in‑depth overview of the association between the STX3 gene (HGNC:11438) and microvillus inclusion disease (MONDO_0009635). Multiple independent studies using both case reports and multi‑patient cohorts have shown that biallelic, loss‑of‑function variants in STX3 underlie a severe autosomal recessive congenital enteropathy. Affected infants typically present with intractable secretory diarrhea, metabolic acidosis (PMID:29282386), failure to thrive, and in some cases, abnormal eye movements (PMID:30909251).

The clinical evidence spans several reports, including a 2017 case report of a Saudi infant with a homozygous STX3 mutation and a subsequent 2019 report noting this as the fifth patient with a STX3 mutation causing variant MVID. In addition, a 2021 multi‑patient study identified ten individuals with biallelic STX3 variants – some of whom exhibited a syndromic form including severe retinal dystrophy – thereby reinforcing the strong genotype‑phenotype correlation (PMID:33974130).

Genetic evidence is bolstered by the identification of recurrent and clearly disruptive variants. In particular, the variant c.739C>T (p.Arg247Ter), noted in independent cohorts, confirms a loss‑of‑function mechanism. Such variants have been observed in multiple unrelated probands with clear autosomal recessive inheritance, providing robust support for the gene‑disease association (PMID:29282386).

Experimental studies have further validated these clinical findings. In vitro and in vivo models have demonstrated that impaired STX3 function disrupts apical membrane trafficking, leading to enterocyte dysfunction consistent with MVID. Cellular assays and animal models have shown that abrogation of STX3 function mirrors the intestinal pathology seen in affected patients, with experimental data correlating well with the clinical phenotype (PMID:10788461, PMID:7768895).

In light of these converging lines of evidence, the overall clinical validity of the association is rated as Strong. Multiple independent probands (approximately 16 across studies PMID:29282386, PMID:30909251, PMID:33974130) and comprehensive functional studies together provide a high level of confidence that biallelic STX3 mutations are pathogenic in microvillus inclusion disease.

The genetic and experimental data provide a coherent narrative: recurrent loss‑of‑function variants in STX3 disrupt protein domains essential for apical trafficking in enterocytes, leading to severe congenital diarrhea and associated complications. While additional variants and phenotypic nuances continue to emerge, the current evidence robustly supports the clinical utility of genetic testing for STX3 variants in patients with early‑onset MVID.

Key take‑home sentence: Routine genetic screening for STX3 loss‑of‑function variants should be considered in infants with intractable diarrhea and metabolic acidosis to facilitate early diagnosis and targeted management of microvillus inclusion disease.

References

• Case reports in gastroenterology • 2017 • Microvillus Inclusion Disease Variant in an Infant with Intractable Diarrhea PMID:29282386
• Journal of neonatal‑perinatal medicine • 2019 • Microvillus inclusion disease, a diagnosis to consider when abnormal stools and neurological impairments run together due to a rare syntaxin 3 gene mutation PMID:30909251
• Human genetics • 2021 • Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early‑onset severe retinal dystrophy in microvillus inclusion disease subjects PMID:33974130
• The Journal of biological chemistry • 2000 • Munc18‑2, a functional partner of syntaxin 3, controls apical membrane trafficking in epithelial cells PMID:10788461
• The Journal of biological chemistry • 1995 • A novel ubiquitous form of Munc‑18 interacts with multiple syntaxins PMID:7768895

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