ArticleAmerican journal of human genetics2009
Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea.
Article in American journal of human genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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62 citing papers in PubMed, 123 citations in OpenAlex.
- Hepatocyte growth factor activator inhibitor-2 rapidly inactivates airway-expressed human type II transmembrane serine proteases.The Journal of biological chemistry · 2026Article
- A biochemical difference between HAI-2 variants causing syndromic and non-syndromic Congenital Sodium Diarrhea.PloS one · 2026Article
- Congenital Diarrhea: A Case Report on Challenges in Both Prenatal and Postnatal Diagnosis.Case reports in obstetrics and gynecology · 2026Article
- Non-Syndromic Congenital Sodium Diarrhoea With a SLC9A3 Gene Variant: A Case Report.Journal of paediatrics and child health · 2025Article
- Article
- GPI-anchored serine proteases: essential roles in development, homeostasis, and disease.Biological chemistry · 2025Review
- Cellular and molecular basis of proximal small intestine disorders.Nature reviews. Gastroenterology & hepatology · 2024Review
- Approach to Congenital Diarrhea and Enteropathies (CODEs).Indian journal of pediatrics · 2024Review
- SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.Human molecular genetics · 2024Article
- Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM.Development (Cambridge, England) · 2023Article
- 150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility.Cell genomics · 2023Article
- Congenital Sodium Diarrhea: Antenatal Diagnosis May Prevent Unnecessary Surgery in the Neonate.AJP reports · 2023Article
- The genetics of monogenic intestinal epithelial disorders.Human genetics · 2023Review
- N-glycosylation on Asn-57 is required for the correct HAI-2 protein folding and protease inhibitory activity.Glycobiology · 2023Article
- Congenital Tufting Enteropathy, a Rare Cause of Diarrhea and Malnourishment in Arab Child with Genetic and Histopathology Investigations.Case reports in pediatrics · 2023Article
- A novel SPINT2 missense mutation causes syndromic congenital sodium diarrhea.World journal of pediatrics : WJP · 2022Article
- Homozygous Missense Epithelial Cell Adhesion Molecule Variant in a Patient with Congenital Tufting Enteropathy and Literature Review.Pediatric gastroenterology, hepatology & nutrition · 2022Review
- Further delineation of SLC9A3-related congenital sodium diarrhea.Molecular genetics & genomic medicine · 2022Article
- The difference in the intracellular Arg/Lys-rich and EHLVY motifs contributes to distinct subcellular distribution of HAI-1 versus HAI-2.Human cell · 2022Article
- Targeted HAI-2 deletion causes excessive proteolysis with prolonged active prostasin and depletion of HAI-1 monomer in intestinal but not epidermal epithelial cells.Human molecular genetics · 2021Article
2 more citing papers are in PubMed but not listed here.
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24 authors at 13 institutions in 9 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion. Defective jejunal brush-border Na(+)/H(+) exchange has been reported in three sporadic patients, but the molecular basis of the disease has not been elucidated. We reviewed data from a large cohort of CSD patients (n = 24) and distinguished CSD associated with choanal or anal atresia, hypertelorism, and corneal erosions--i.e., a syndromic form of CSD--occurring in ten families from an isolated form--i.e., classic CSD--presenting in seven families. Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition. A genome-wide SNP scan was applied and identified a homozygous c.593-1G-->A splicing mutation in SPINT2, encoding a Kunitz-type serine-protease inhibitor, in one extended kindred with syndromic CSD. The same mutation and four distinct, homozygous or compound heterozygous mutations (p.Y163C, c.1A-->T, c.337+2T-->C, c.553+2T-->A) were identified in all syndromic patients. No SPINT2 mutations were found in classic-CSD patients. SPINT2 mutations were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro. We delineate syndromic CSD as a distinct disease entity caused by SPINT2 loss-of-function mutations. SPINT2 mutations might lead to an excess of yet unknown serine protease activity in affected tissues.
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