Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea

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Item Type:	Article
Title:	Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea
Creators Name:	Heinz-Erian, P., Mueller, T., Krabichler, B., Schranz, M., Becker, C., Rueschendorf, F., Nuernberg, P., Rossier, B., Vujic, M., Booth, I.W., Holmberg, C., Wijmenga, C., Grigelioniene, G., Kneepkens, C.M., Rosipal, S., Mistrik, M., Kappler, M., Michaud, L., Doczy, L.C., Siu, V.M., Krantz, M., Zoller, H., Utermann, G. and Janecke, A.R.
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.
Keywords:	Amino Acid Sequence, Imperforate Anus, Base Sequence, Chromosome Mapping, Cohort Studies, DNA Mutational Analysis, Diarrhea, Feces, Recessive Genes, Newborn Infant, Malabsorption Syndromes, Membrane Glycoproteins, Molecular Sequence Data, Mutation, Pedigree, Messenger RNA, Sodium, Survival Analysis
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	84
Number:	2
Page Range:	188-196
Date:	13 February 2009
Official Publication:	https://doi.org/10.1016/j.ajhg.2009.01.004
PubMed:	View item in PubMed

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