Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease.
Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.
Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Paris, France.
B
B
Doray
R
R
Salomon
J
J
Amiel
A
A
Pelet
R
R
Touraine
M
M
Billaud
T
T
Attié
B
B
Bachy
A
A
Munnich
S
S
Lyonnet
D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D051101:Neurturin; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
D017931:DNA Primers; D029721:Drosophila Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; C495053:NRTN protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; D011518:Proto-Oncogene Proteins; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila