Molecular Basis of Disease

In 1993, the RET protooncogene ("rearranged during transfection"), located on chromosome 10q11,was cloned and characterized as encoding a transmembrane tyrosine

RET protooncogene

RET protooncogene

Figure 20-2. Diagram of RET gene product indicating the relative location of germline mutations characterized in patients with MEN2. Ovals are numbered to represent the codons that commonly contain germline missense mutations associated with MEN2A and FMTC. Diamonds are numbered to represent the codon location of germline mutations in MEN2B.Triangles indicate the positions of mutations in hereditary Hirschsprung disease. (From Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol 2000;18:324-332, copyright © 2000. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley and Sons, Inc.)

Figure 20-2. Diagram of RET gene product indicating the relative location of germline mutations characterized in patients with MEN2. Ovals are numbered to represent the codons that commonly contain germline missense mutations associated with MEN2A and FMTC. Diamonds are numbered to represent the codon location of germline mutations in MEN2B.Triangles indicate the positions of mutations in hereditary Hirschsprung disease. (From Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol 2000;18:324-332, copyright © 2000. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley and Sons, Inc.)

kinase with a cysteine-rich extracellular receptor domain (Figure 20-2).20,21 RET spans 60kb with 21 exons encoding a protein of approximately 1,100 amino acids.6 Glial cell derived neurotrophic factor (GDNF) and neurturin are two ligands for the RET receptor domain.22 The ligands initiate homodimerization of RET protein molecules resulting in phosphorylation and activation of the tyrosine kinase domain, leading to downstream signal transduction.22 Missense mutations in the RET gene were characterized in individuals with the MEN2 syndromes20,21,23,24 with a very restricted pattern of variations (Figure 20-2). In patients with MEN2A, nearly all the mutations in this gene are missense mutations localized to five conserved cysteine residues in RET exons 10 and 11 (Table 20-1) in a cysteine-rich extracellular domain adjacent to the transmembrane domain of the RET protein (Figure 20-2).20,21,23 Most of these mutations produce constitutive dimerization and increased kinase activation of the aberrant RET protein.25 Individuals with only FMTC have missense mutations in these same cysteine codons or in a few additional codons (768 and 804) located in exons 13 and 14 (Table 20-1), which specify intracellular portions of the RET protein next to the transmembrane domain (Figure 20-2).26,27 Nearly 95% of all patients diagnosed with MEN2B have been characterized with a single missense mutation in codon 918 of RET exon 16, M918T, replacing a methionine residue with a threonine.23,24 This variant, in the intracellular tyrosine kinase catalytic domain (Figure 20-2), alters substrate recognition, which leads to cellular transforma-tion.25 In each case, the mutation produces a gain-of-

Table 20-1. Common RET Gene Mutations in

MEN2 and Associated Clinical Phenotypes

Amino Acid Substitutionf

RET location

Codon*

Y F TAC TTC

GGC

CGC

S W D M L T TCC or AGC TGG GAC ATG TTG ACG

Exon 10

C609 TGC

2A, FMTC 2A HSCR

2A

2A

—* HSCR

C611 TGC

2A 2A

FMTC

2A

2A 2A

C618 TGC

FMTC 2A

2A, FMTC

2A, FMTC

2A, FMTC —* HSCR

C620 TGC

2A FMTC

2A

2A, FMTC HSCR

FMTC 2A, HSCR

Exon 11

C634 TGC

2A 2A

2A

2A, FMTC

2A, FMTC 2A

Exon 13

E768 GAG

FMTC —* —* —*

Exon 14

V804 GTG

—* FMTC, 2A FMTC —*

Exon 16

M918 ATG

—* —* —* 2B

*The normal codon and sequence is listed in the Codon column.

fThe Amino Acid Substitutions (single-letter abbreviations) and codon triplet sequences that result from the point mutations at each normal codon are listed across the top of the table.

i Some substitutions have not been described at every codon and are indicated by a dash.

The clinical phenotypes that have been described for each substitution are displayed in the grid. 2A, MEN2A;FMTC, familial medullary thyroid carcinoma;HSCR, Hirschsprung disease;2B, MEN2B. Example: C609Y,TGC ^ TAC has been described in cases of MEN2A,FMTC, and HSCR.

More extensive lists can be viewed at the Human Gene Mutation Database Cardiff Web site for RET (http://archive.uwcm.ac.uk/ uwcm/mg/search/120346.html) and the RET Gene Card (Weizmann) (http://bioinfo.weizmann.ac.il/cards-bin/carddisp7RET).

function change for the aberrant RET protein. Online information about many other RET mutations is available from the Human Gene Mutation Database Cardiff (http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120346. html) and the Weizmann Institute of Science GeneCards (http://www.genecards.org/cgi-bin/carddisp-pl?=RET).

Hirschsprung disease (HSCR) is also associated with somatic or germline RET mutations, either in codons 609, 618, or 620, or throughout other regions of the RET gene.28'29 Some families have been described in which HSCR cosegregates with either MEN2A or FMTC.30 RET mutations in patients with HSCR may produce either loss or gain of RET protein function and include frameshift and nonsense mutations. Papillary thyroid carcinoma is associated with somatic gene rearrangements of the RET

gene.31

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