title: Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea.
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.
authors.affiliation: Department of Pediatrics II, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Heinz-Erian
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Birgit
authors.initials: B
authors.lastname: Krabichler
authors.forename: Melanie
authors.initials: M
authors.lastname: Schranz
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Bernard
authors.initials: B
authors.lastname: Rossier
authors.forename: Mihailo
authors.initials: M
authors.lastname: Vujic
authors.forename: Ian W
authors.initials: IW
authors.lastname: Booth
authors.forename: Christer
authors.initials: C
authors.lastname: Holmberg
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: C M Frank
authors.initials: CM
authors.lastname: Kneepkens
authors.forename: Stefan
authors.initials: S
authors.lastname: Rosipal
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.forename: Matthias
authors.initials: M
authors.lastname: Kappler
authors.forename: Laurent
authors.initials: L
authors.lastname: Michaud
authors.forename: Ludwig-Christoph
authors.initials: LC
authors.lastname: Dóczy
authors.forename: Victoria Mok
authors.initials: VM
authors.lastname: Siu
authors.forename: Marie
authors.initials: M
authors.lastname: Krantz
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.forename: Gerd
authors.initials: G
authors.lastname: Utermann
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
mesh_terms: D000595:Amino Acid Sequence; D001006:Anus, Imperforate / Q000235:genetics / Q000401:mortality / Q000473:pathology; D001483:Base Sequence; D002874:Chromosome Mapping; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003967:Diarrhea / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005243:Feces / Q000737:chemistry; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008286:Malabsorption Syndromes / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C109148:SPINT2 protein, human; D012964:Sodium