Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea.
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.
Heinz-Erian
Peter
P
Department of Pediatrics II, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Müller
Thomas
T
Krabichler
Birgit
B
Schranz
Melanie
M
Becker
Christian
C
Rüschendorf
Franz
F
Nürnberg
Peter
P
Rossier
Bernard
B
Vujic
Mihailo
M
Booth
Ian W
IW
Holmberg
Christer
C
Wijmenga
Cisca
C
Grigelioniene
Giedre
G
Kneepkens
C M Frank
CM
Rosipal
Stefan
S
Mistrik
Martin
M
Kappler
Matthias
M
Michaud
Laurent
L
Dóczy
Ludwig-Christoph
LC
Siu
Victoria Mok
VM
Krantz
Marie
M
Zoller
Heinz
H
Utermann
Gerd
G
Janecke
Andreas R
AR
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
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C109148:SPINT2 protein, human; D012964:Sodium