Unilateral Renal Agenesis in a Family with Medullary Thyroid Carcinoma

Lorè, F; Cairano, G. Di; Talidis, Filotas

doi:10.1056/nejm200004203421615

Cited by 32 publications

(19 citation statements)

References 5 publications

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“…Recently, an association between renal abnormalities and the Janus mutation in ret has been established (36). During embryogenesis, RET is expressed in the embryonic kidney by the tips of the ureteric bud.…”

Section: Discussionmentioning

confidence: 99%

Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Arighi

Popsueva

Degl’Innocenti

et al. 2004

Molecular Endocrinology

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Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor, cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma. Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20-30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic Janus mutation at Cys620 of RET. In Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Arighi

Popsueva

Degl’Innocenti

et al. 2004

Molecular Endocrinology

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“…MEN2A arises as a result of activating mutation of the RET, but the mechanism of RET activation by these mutations is uncertain. RET protein is a tyrosine kinase-like cell surface receptor expressed primarily in neural crest and urogenital precursor cells [17][18]. Like other tyrosine kinase receptors, the structural domains of polypeptide products consist of an extracellular ligand-binding region with a cadherin-like site, as well as a large juxtamembrane cysteine-rich domain, a transmembrane region, and a conserved intracellular portion containing the tyrosine kinase domain (TK) [19].…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation (D631del) of the RET Gene Was Associated with MEN2A in a Chinese Pedigree

et al. 2009

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Abstract. Germline mutations in the RET proto-oncogene (RET gene) are well documented as the genetic causes of multiple endocrine neoplasia type 2A (MEN2A). We performed genetic analysis by direct RET gene mutation analysis in a Chinese MEN2A family and compared these results with biochemical screening tests and pathological examinations. Twenty-one exons and flanking introns of the RET gene were amplified using polymerase chain reaction (PCR). The PCR products were subjected to sequencing directly, or cloned into pGEM-T plasmids and sequenced. Restriction fragment length polymorphism (RFLP) was employed to confirm the mutation on the RET sequence. A novel heterozygous mutation of a 3-bp (GAC) deletion at codon 631 (D631del) of exon 11, resulting in the deletion of an aspartic acid at the locus, was identified in four MEN2A patients and one phenotypically normal family member. The average clinical onsetage of four MEN2A patients was 33.7 years, no cervical lymph node metastasis was found in MEN2A patients with medullary thyroid carcinoma in the family. The study indicated that the novel heterozygous deletion mutation at D631 of RET gene was co-segregated with MEN2A phenotype and promoted the development of MEN2A. This report is the first description of the D631del mutation in the family with MEN2A.

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“…Although there is only limited evidence that links mutations in Ret to kidney and urinary tract malformations in humans [Loré et al, 2000[Loré et al, , 2001 and Ret mutations have not been identified in the only VUR family studied [Shefelbine et al, 1998], several investigations with animal models suggested that Ret dysfunction may be responsible for UB branching, distal ureter abnormalities, and VUR [Shakya et al, 2005;Yu et al, 2004, Batourina et al, 2002Schuchardt et al, 1996]. UB outgrowth is inhibited in ret-null mice; however, their metanephric mesenchyme is still responsive to inductive signals [Murawski and Gupta, 2006;Costantini and Shakya, 2006;Pachnis et al, 1993].…”

Section: Introductionmentioning

confidence: 99%

RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

et al. 2008

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Primary vesicoureteral reflux (pVUR) is a common, genetically heterogeneous congenital urinary tract abnormality in children. It causes urine to flow backward from the bladder to the ureter due to a developmental defect at the vesicoureteral junction, whose formation requires rearrangement during transformation (Ret)-mediated signaling pathways. To study the genetic causes of pVUR in Quebec patients, we used a sequencing-based candidate gene approach to screen the RET gene and found that 83 out of 118 pVUR patients are carriers of the rare A allele of single nucleotide polymorphism (SNP) rs1799939:G>A that results in a Gly691Ser mutation, a statistically significant increase in allelic frequency, that is absent at six flanking RET SNPs tested. Ser691 is a predicted phosphorylation site and our analysis of transfected cells showed that the Gly691Ser Ret mutant can efficiently interact and associate with a 75-80-kD tyrosine phosphorylated cellular protein, an event not seen with wild-type Ret. This interaction and/or the steric or electric hindrance created by phospho-Ser691 may interfere with the known regulatory functions of the normally phosphorylated phospho-Tyr687 and phospho-Ser696 on the cytoskeleton actin reorganization that are responsible for cell motility and morphology, which consequently may lead to the deficiency in ureteral development observed in pVUR. Our study demonstrates that the Ret Gly691Ser mutation is associated with pVUR and may be one of the genetic causes of this condition in the French-Canadian population in Quebec.

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Unilateral Renal Agenesis in a Family with Medullary Thyroid Carcinoma

Cited by 32 publications

References 5 publications

Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

Biological Effects of the Dual Phenotypic Janus Mutation of ret Cosegregating with Both Multiple Endocrine Neoplasia Type 2 and Hirschsprung’s Disease

A Novel Mutation (D631del) of the RET Gene Was Associated with MEN2A in a Chinese Pedigree

RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec

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