A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

Vanhorne, Judith B.; Andrew, Scott D.; Harrison, Karen J.; Taylor, Sherryl A. M.; Thomas, Bradley; McDonald, Thomas J.; Ainsworth, Peter; Mulligan, Lois M.

doi:10.1038/sj.onc.1207826

Cited by 12 publications

(9 citation statements)

References 21 publications

(25 reference statements)

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“…Some other reports on FMTC families have speculated about the possible involvement of certain RET polymorphisms, such as L769L (c.2307T➝G, exon 13) or S836S (c. 2439C➝T, exon 14), in the reduced penetrance of the disease among carriers of mutations affecting the 804 codon (20,21). Results derived from a recent study revealed the over-representation or exclusive presentation of some variants within the GFRA4 gene (encoding a co-receptor of RET) in MEN 2 patients, when comparing with their healthy relatives, thus suggesting a putative modifying role for such polymorphisms in MEN 2 (22).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients

Fernández

Navarro²,

Antiñolo³

et al. 2006

Int J Mol Med

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Abstract. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome, which is divided into three subtypes: MEN 2A, MEN 2B and familial medullary thyroid cancer (FMTC). Approximately 92% of MEN 2 cases are caused by mutations in exons 10, 11, 13-16 of the RET proto-oncogene. There exists inter-and intra-familial phenotypic variability among the MEN 2 families, even when the disease is caused by the same RET mutation, suggesting a role for genetic modifiers, such as polymorphisms/haplotypes. We have sought to determine the frequency and position of RET germline mutations in a cohort of 114 Spanish probands with any sign of MEN 2, and to search for putative modifier loci. Mutational screening of RET revealed 9 different mutations, present in 26 of the 114 probands (22.8%). In addition, distributions of 8 RET polymorphisms and the haplotypes comprising them, were studied in the context of the families positive for RET mutational screening, in order to evaluate them as genetic modifiers. The relationship between RET mutation type and presence of a polymorphism/haplotype was analyzed. The relationship between the presence of pheochromocytoma (PC) and/or hiperparathyroidism (HPT) in carriers of the same RET mutation, and the genotype for the specific variants was also studied. The results derived from those analyses revealed no associations of any variant/haplotype to a specific mutation or to the clinical presentation. Nevertheless, these observations do not permit us to exclude the possible role of other variants in RET or other related genes, in the final presentation of the disease.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients

Fernández

Navarro²,

Antiñolo³

et al. 2006

Int J Mol Med

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“…These residues may be involved in the formation of intermolecular cysteine bridges, thereby giving rise to dimeric GFRa4 receptor complexes in the absence of PSPN (Figure 1e). Recently, a mutation that gives rise to two putative forms of soluble GFRa4 receptors was reported to be involved in a more aggressive disease course of MEN 2 (Vanhorne et al, 2005). As these mutated forms of the GFRa4 receptor also harbor non-conserved cysteine residues in D3 (Figure 1a), it remains to be determined if the described phenotype could be caused by the formation of covalently linked dimeric GFRa4 receptor complexes.…”

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confidence: 99%

“…A schematic picture of the mouse GFRa4 splicing variants is shown in Figure 1d. Recently, a mutation, which may contribute to a more aggressive disease course of MEN 2, was identified in human GFRa4 (Vanhorne et al, 2005). The mutation consists of a 7 bp insertion that causes a frameshift in all of the human GFRa4 splice variants.…”

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confidence: 99%

“…The biochemical detection of activated downstream signalling was Figure 1 Molecular characterization of soluble GFRa4. (a) A sequence alignment of D2 and D3 domains of rat GFRa1, mouse GPIanchored GFRa4 (mGFRa4-GPI), mouse soluble GFRa4 (mGFRa4-sol), the putative human soluble GFRa4 (hGFRa4-sol), as well as the two putative soluble mutant forms of human GFRa4 (hSCa and hSCb) (Vanhorne et al, 2005). The conserved cysteines are highlighted in yellow, and the putative disulfide bridges are numbered as in the homologous rat GFRa1 D3 (Leppa¨nen et al, 2004) and in human GFRa3 D2 (Wang et al, 2006) shown in (c).…”

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confidence: 99%

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The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin

et al. 2007

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Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) all signal through the transmembrane receptor tyrosine kinase RET. The signalling complex consists of GFLs, GPI-anchored ligand binding GDNF family receptor alphas (GFRas) and RET. Signalling via RET is required for the development of the nervous system and the kidney, as well as for spermatogenesis. However, constitutive activation of RET is implicated as a cause in several diseases. Mutations of the RET proto-oncogene cause the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). Recently, it has been suggested that mutations in the persephin binding GFRa4 receptor may have a potentially modifying role in MEN 2. Several naturally occurring, different splice variants of the mammalian GFRa4 have been reported. A 7 bp insertion-mutation in the human GFRa4 gene causes a shift of reading frame and thereby changes the balance between the transcripts encoding GPI-anchored and soluble GFRa4 receptors. We report here that the mammalian soluble GFRa4 can activate RET independently of its preferential ligand, persephin. Our data show that soluble GFRa4 can associate with, and induce, phosphorylation of RET. In addition, our data show that this isoform of GFRa4 can induce downstream signalling, as well as neuronal survival and differentiation, in the absence of persephin. These results suggest that, in line with the previous report, GFRa4 may be a candidate gene for, or modifier of, the MEN 2 diseases.

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“…However, the intrafamilial and interfamilial phenotypic variability concerning the age of onset and tumor spectrum suggest that genetic modifying factors exist (5), and this has been confirmed using animal models (6). However, data on possible genetic factors involved in clinical MEN2 variability are scarce (7,8), which is partially due to the low prevalence of this syndrome (1:30,000; ref. 9).…”

Section: Introductionmentioning

confidence: 99%

Association Study of 69 Genes in the Ret Pathway Identifies Low-penetrance Loci in Sporadic Medullary Thyroid Carcinoma

Ruiz‐Llorente

Montero‐Conde²,

Milne³

et al. 2007

Cancer Research

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To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene-and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. [Cancer Res 2007;67(19):9561-7]

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A model for GFRα4 function and a potential modifying role in multiple endocrine neoplasia 2

Cited by 12 publications

References 21 publications

Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients

Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients

The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin

Association Study of 69 Genes in the Ret Pathway Identifies Low-penetrance Loci in Sporadic Medullary Thyroid Carcinoma

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