TMPRSS15 and Congenital Enteropathy due to Enteropeptidase Deficiency

TMPRSS15 (HGNC:9490) is implicated in congenital enteropathy due to enteropeptidase deficiency (MONDO_0009173), a rare autosomal recessive disorder manifesting with intractable diarrhea, hypoproteinemia, failure to thrive, and vomiting (PMID:33061943). Two independent case reports provide compelling evidence: one describes a Chinese child who is compound heterozygous for TMPRSS15 variants and another details a patient with a homozygous nonsense mutation. Both studies report variants that lead to loss‑of‑function in the gene, and their findings are supported by functional assays.

Genetic evidence is robust with at least three probands identified carrying pathogenic variants. In one study, the patient harbored the variants c.1921G>A and c.2396T>A (p.Val799Asp), with the latter selected here as the representative alteration. The variant c.1921G>A disrupts a splicing donor site resulting in exon skipping, while c.2396T>A (p.Val799Asp) has been shown to decrease TMPRSS15 protein expression and enzymatic activity by approximately 29% and 37%, respectively (PMID:33061943). The autosomal recessive inheritance model is reinforced by the compound heterozygous as well as homozygous states found in affected children.

Functional investigations further substantiate the gene‐disease relationship. In vitro minigene assays confirmed that the c.1921G>A variant causes abnormal splicing, and protein expression analyses have convincingly shown reduced enzyme activity associated with the c.2396T>A (p.Val799Asp) variant. These studies delineate a clear loss‑of‑function mechanism that aligns well with the clinical phenotype of enteropeptidase deficiency.

The convergence of genetic and experimental evidence supports a Strong clinical validity classification for the TMPRSS15–congenital enteropathy association. Although the total number of reported cases is modest, the consistency across independent reports and the robust in vitro data underscore the reliability of TMPRSS15 testing for diagnostic decision‑making.

In summary, TMPRSS15 is firmly established as a causative gene in congenital enteropathy due to enteropeptidase deficiency, and its evaluation is highly valuable for clinical diagnosis, commercial genetic testing, and future research endeavors.

Key Take‑home sentence: Convergent genetic and functional findings decisively support TMPRSS15 as a critical gene in congenital enteropathy due to enteropeptidase deficiency, underscoring its clinical utility in guiding diagnosis and management.

References

• Frontiers in Genetics • 2020 • Novel Compound Heterozygous TMPRSS15 Gene Variants Cause Enterokinase Deficiency PMID:33061943
• Pediatric Dermatology • 2023 • Enterokinase deficiency with novel TMPRSS15 gene mutation masquerading as acrodermatitis enteropathica PMID:36410965

Evidence Based Scoring (AI generated)