Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea

Am J Hum Genet. 2009 Feb;84(2):188-96. doi: 10.1016/j.ajhg.2009.01.004. Epub 2009 Jan 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anus, Imperforate / genetics
  • Anus, Imperforate / mortality
  • Anus, Imperforate / pathology
  • Base Sequence
  • Chromosome Mapping
  • Cohort Studies
  • DNA Mutational Analysis
  • Diarrhea / genetics*
  • Diarrhea / mortality
  • Diarrhea / pathology
  • Feces / chemistry
  • Female
  • Genes, Recessive
  • Humans
  • Infant
  • Infant, Newborn
  • Malabsorption Syndromes / genetics*
  • Malabsorption Syndromes / mortality
  • Malabsorption Syndromes / pathology
  • Male
  • Membrane Glycoproteins / genetics*
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • RNA, Messenger / genetics
  • Sodium / metabolism*
  • Survival Analysis


  • Membrane Glycoproteins
  • RNA, Messenger
  • SPINT2 protein, human
  • Sodium