A homozygous missense mutation in the tyrosine E kinase domain of the RET proto-oncogene in an infant with total intestinal aganglionosis

The American Journal of Gastroenterology
T ShimotakeN Iwai

Abstract

Germline mutations of the RET proto-oncogene (RET), its ligand glial cell-derived neurotrophic factor (GDNF), and neurturin (NTN) gene have been reported in patients with Hirschsprung's disease. A targeted mutation in the tyrosine kinase domain of RET produced total intestinal aganglionosis and renal agenesis in homozygous transgenic mice. Here we describe a homozygous mutation of the human gene for the RET tyrosine kinase domain that was present in a male neonate with total intestinal aganglionosis. Gut wall biopsy specimens from the stomach to the anorectum showed no ganglion cells. No urinary tract abnormalities were detected. Genomic DNAs were isolated from peripheral blood lymphocytes of the infant and his parents. DNA sequences of all the RET/GDNF/NTN coding regions were determined using a direct DyeDeoxy Terminator Cycle method. A homozygous missense mutation (CGG-to-TGG) at RET codon 969 was identified in this patient, which resulted in an amino acid change from arginine to tryptophan. No germline RET/GDNF/NTN mutations were found in his parents. In this case, the homozygous RET mutation seemed to cause a critical alteration of the Ret tyrosine kinase activity, which resulted in total intestinal aganglionosis but not re...Continue Reading

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Citations

Nov 9, 2006·European Journal of Human Genetics : EJHG·Lina Basel-VanagaiteStanislas Lyonnet
Feb 11, 2015·The Journal of Clinical Investigation·Marina AvetisyanRobert O Heuckeroth
Sep 5, 2013·Clinical Pediatrics·Deepika D'Cunha BurkardtPhilip K Frykman
Dec 12, 2003·World Journal of Gastroenterology : WJG·Xiang-Long DuanGuo-Wei Li
May 11, 2005·Familial Cancer·Christian A Koch
Jul 15, 2015·Pediatric Surgery International·C Tomuschat, P Puri
May 4, 2013·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jonathan I Lake, Robert O Heuckeroth
Oct 13, 2006·Current Opinion in Gastroenterology·William M Belknap
Nov 20, 2002·World Journal of Gastroenterology : WJG·Ji-Cheng LiMin-Ju Li

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