PMID- 10484767
OWN - NLM
STAT- MEDLINE
DCOM- 19991216
LR  - 20190607
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 11
DP  - 1999 Oct
TI  - Two distinct mutations of the RET receptor causing Hirschsprung's disease impair 
      the binding of signalling effectors to a multifunctional docking site.
PG  - 1989-99
AB  - The RET gene codes for a transmembrane tyrosine kinase which is a subunit of a
      multimeric complex that acts as a receptor for four structurally related
      molecules: the glial cell line-derived neurotrophic factor (GDNF), neurturin,
      artemin and persephin. Germline mutations of RET cause a dominantly inherited
      dysgenesis of the enteric nervous system known as Hirschsprung's disease (HSCR;
      aganglionosis megacolon). The majority of HSCR mutations results either in a
      reduction of dosage of the RET protein or in the loss of RET function. Two novel 
      distinct mutations of RET that led either to the deletion of codon 1059 (denoted 
      Delta1059) or to the substitution of a Pro for Leu1061 have been identified in
      five HSCR families. In one large pedigree, two children born from asymptomatic
      consanguineous parents presented a severe form of HSCR and were found to carry
      the mutation at codon 1061 in the homozygous state. A tyrosine residue at
      position 1062 is an intracytoplasmic docking site that enables RET to recruit
      several signalling molecules, including the Shc adaptor protein. We now report
      that both HSCR mutations impair the fixation of Shc to RET and consequently
      prevent its phosphorylation. In addition, quantitative analysis in PC12 cells
      reveals that mutation Delta1059 inactivates the ability of RET to transduce a
      downstream signal whereas mutation L1061P only partially inhibits the signalling 
      of RET. Finally, we provide evidence that these effects are partly mediated via
      the disruption of the RET/Shc interaction. Collectively, these results
      demonstrate that HSCR can be ascribed to mutations of RET which interfere with
      the binding of transduction effectors, such as Shc, and further provide a
      biochemical explanation for the phenotype of patients carrying a homozygous
      mutation at codon 1061. Finally, these data indicate that Y1062 is a
      multifunctional docking site that confers to RET the capacity to engage
      downstream signalling pathways which exert a crucial role during enteric
      neurogenesis.
FAU - Geneste, O
AU  - Geneste O
AD  - Laboratoire de Genetique, CNRS UMR5641, 8 avenue Rockefeller, Lyon 69373 Cedex
      08, France,
FAU - Bidaud, C
AU  - Bidaud C
FAU - De Vita, G
AU  - De Vita G
FAU - Hofstra, R M
AU  - Hofstra RM
FAU - Tartare-Deckert, S
AU  - Tartare-Deckert S
FAU - Buys, C H
AU  - Buys CH
FAU - Lenoir, G M
AU  - Lenoir GM
FAU - Santoro, M
AU  - Santoro M
FAU - Billaud, M
AU  - Billaud M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Codon)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Glial Cell Line-Derived Neurotrophic Factor Receptors)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (SHC1 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Shc1 protein, mouse)
RN  - 0 (Shc1 protein, rat)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Ret protein, Drosophila)
RN  - EC 2.7.10.1 (Ret protein, mouse)
RN  - EC 2.7.10.1 (Ret protein, rat)
SB  - IM
MH  - 3T3 Cells
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites/genetics
MH  - Codon/*genetics
MH  - Consanguinity
MH  - DNA Mutational Analysis
MH  - *Drosophila Proteins
MH  - Female
MH  - Glial Cell Line-Derived Neurotrophic Factor Receptors
MH  - Hirschsprung Disease/*genetics
MH  - Humans
MH  - Infant, Newborn
MH  - Macromolecular Substances
MH  - Male
MH  - Mice
MH  - PC12 Cells
MH  - Pedigree
MH  - Phosphorylation
MH  - *Point Mutation
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins c-ret
MH  - Rats
MH  - Receptor Protein-Tyrosine Kinases/*genetics
MH  - Recombinant Fusion Proteins/metabolism
MH  - *Sequence Deletion
MH  - Shc Signaling Adaptor Proteins
MH  - Signal Transduction/*genetics
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
MH  - Transfection
EDAT- 1999/09/15 09:00
MHDA- 2000/04/01 09:00
CRDT- 1999/09/15 09:00
PHST- 1999/09/15 09:00 [pubmed]
PHST- 2000/04/01 09:00 [medline]
PHST- 1999/09/15 09:00 [entrez]
AID - ddc243 [pii]
AID - 10.1093/hmg/8.11.1989 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Oct;8(11):1989-99. doi: 10.1093/hmg/8.11.1989.