SPINT2 – Syndromic Congenital Sodium Diarrhea

Syndromic congenital sodium diarrhea (SCSD) is a rare, autosomal recessive disorder characterized by intractable secretory diarrhea of infancy with choanal atresia, corneal erosions, and anal atresia. Loss-of-function variants in SPINT2, encoding the Kunitz-type serine protease inhibitor HAI-2, underlie SCSD by disrupting epithelial sodium homeostasis and protease regulation. The association between SPINT2 and SCSD has been supported by multiple independent case series, segregation in extended pedigrees, and consistent in vitro functional data, establishing a definitive gene–disease relationship.

Initial mapping in a cohort of 24 congenital sodium diarrhea patients, including 10 families with the syndromic form, identified homozygous splicing and missense SPINT2 mutations segregating with disease ([PMID:19185281]). All syndromic individuals harbored bi-allelic SPINT2 variants such as c.593-1G>A and c.337+2T>C, whereas classic CSD cases lacked SPINT2 mutations. Subsequently, 34 unrelated SCSD probands were reported carrying 13 distinct pathogenic SPINT2 alleles (splice, nonsense, frameshift, initiation codon, and missense) ([PMID:30445423]).

Segregation analysis in at least 10 consanguineous and non-consanguineous families confirmed autosomal recessive inheritance with co-segregation of SPINT2 variants and SCSD phenotypes ([PMID:19185281]). The variant spectrum includes 4 missense mutations in Kunitz domain 2, 2 splice-site changes, and several loss-of-function alleles. A recurrent founder splice-site mutation c.593-1G>A occurs in multiple geographic isolates.

Functional assays demonstrate that SCSD-associated missense variants in Kunitz domain 2 (e.g., c.488A>G (p.Tyr163Cys)) impair the ability of HAI-2 to inhibit prostasin, while preserving matriptase inhibition, indicating selective loss of protease regulation in enterocytes ([PMID:30445423]). Loss-of-function variants abolish trypsin inhibition and protein synthesis in vitro, confirming haploinsufficiency as the pathogenic mechanism ([PMID:19185281]).

Recent cellular models using HAI-2-knockout Caco-2 cells engineered to express SCSD-associated SPINT2 mutants revealed abnormal disulfide-linked oligomerization, defective N-glycosylation, and failure to suppress prostasin overactivity, linking misfolding and maturation defects to disease pathogenesis ([PMID:38271183]). Restoration of mature HAI-2 rescued protease inhibition and normalized sodium transport in vitro.

Isolated choanal or gastrointestinal atresias without sodium diarrhea have been investigated for SPINT2 mutations; only 1 of 19 non-SCSD atresia cases carried a heterozygous c.593-1G>A variant without clear clinical impact, indicating that SPINT2 defects specifically cause the syndromic form rather than isolated atresias ([PMID:29499739]).

In summary, biallelic SPINT2 variants cause SCSD through a loss-of-function mechanism, supported by definitive genetic and functional evidence. SPINT2 sequencing should be incorporated into diagnostic panels for neonatal secretory diarrhea with atresias. Key Take-home: SPINT2 testing enables accurate diagnosis and informs management of syndromic congenital sodium diarrhea.

References

• American Journal of Human Genetics • 2009 • Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea. PMID:19185281
• Human Molecular Genetics • 2019 • SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase. PMID:30445423
• Human Molecular Genetics • 2024 • SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation. PMID:38271183
• European Journal of Medical Research • 2018 • Isolated choanal and gut atresias: pathogenetic role of serine protease inhibitor type 2 (SPINT2) gene mutations unlikely. PMID:29499739

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