Ancestral RET haplotype associated with Hirschsprung's disease shows linkage disequilibrium breakpoint at -1249

Navarro²,

Antiñolo³

et al. 2006

Int J Mol Med

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.

“…2). The values of frequency were very similar to those obtained in the general Spanish population (28,29,31,32).…”

Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Evaluation Of Ret Variants As Modifier Loci For Men 2a or Fmtcmentioning

confidence: 99%

See 1 more Smart Citation

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

Navarro²,

Antiñolo³

et al. 2006

Int J Mol Med

“…We sought to analyze the distribution of eight RET single nucleotide polymorphisms (SNPs) in the isolated INDB and HSCR+INDB groups, and to compare this with the available data for isolated HSCR patients and controls derived from our previous studies (7,11). Selection of the variants was based on their previously reported association with either HSCR or another disease, such as sporadic medullary thyroid cancer, papillary thyroid cancer or pheochromocytoma (5)(6)(7)(11)(12)(13)(14).…”

Section: Selection and Genotyping Of Ret Sequence Variantsmentioning

confidence: 99%

“…Selection of the variants was based on their previously reported association with either HSCR or another disease, such as sporadic medullary thyroid cancer, papillary thyroid cancer or pheochromocytoma (5)(6)(7)(11)(12)(13)(14). Large scale genotyping of all these RET SNPs was performed using TaqMan-based techniques for allelic discrimination (TaqMan ® SNP Genotyping Assay, Applied Biosystems, Foster City, CA) according to the manufacturer's recommendations.…”

Section: Selection and Genotyping Of Ret Sequence Variantsmentioning

confidence: 99%

Is the RET proto-oncogene involved in the pathogenesis of intestinal neuronal dysplasia type B?

Sánchez-Mejías²,

Ruiz-Ferrer³

et al. 2009

Mol Med Rep

Abstract. Hirschsprung disease (HSCR) is defined by the absence of intramural ganglia of Meissner and Auerbach along variable lengths of the gastrointestinal tract. Intestinal neuronal dysplasia (IND) type B is characterized by the malformation of the parasympathetic submucous plexus of the gut. A connection appears to exist between these two enteric nervous system abnormalities. Due to the major role played by the RET proto-oncogene in HSCR, we sought to determine whether this gene was also related to INDB. dHPLC techniques were employed to screen the RET coding region in 23 patients presenting with INDB and 30 patients with a combined HSCR+INDB phenotype. In addition, eight RET single nucleotide polymorphisms (SNPs) were strategically selected and genotyped by TaqMan technology. The distribution of SNPs and haplotypes was compared among the different groups of patients (INDB, HSCR+INDB, HSCR) and the controls. We found several RET mutations in our patients and some differences in the distribution of the RET SNPs among the groups of study. Our results suggest an involvement of RET in the pathogenesis of intestinal INDB, although by different molecular mechanisms than those leading to HSCR. Further investigation is warranted to elucidate these precise mechanisms and to clarify the genetic nature of INDB.

Association of X‐linked hydrocephalus and Hirschsprung disease: Report of a new patient with a mutation in the L1CAM gene

American J of Med Genetics Pt A

Núñez-Torres

García‐Díaz

et al. 2012

X-linked hydrocephalus (XLH) has an incidence of 1/30,000 male births and is characterized by intellectual disability, spastic paraplegia, adducted thumbs, and agenesis of corpus callosum, and/or corticospinal tract. The great proportion of cases is ascribed to loss of function mutations of L1CAM gene. Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract and has incidence of about 1/5,000. Although with several genes involved in its pathogenesis, the major HSCR gene is the RET proto-oncogene. To date only a few patients have been reported with both phenotypes and mutations in the L1CAM gene. In this report, we describe a new patient with concurrent XLH and HSCR. L1CAM mutational screening showed the presence of the G698R hemizygous mutation, which is a deleterious substitution affecting a key residue necessary for the correct folding of the protein. Moreover, the patient also carried the transcriptional enhancer RET mutation (c.73 + 9277T > C) in heterozygosis. We speculate that both the RET enhancer variant, and the L1CAM mutation may act in combination to produce the enteric phenotype, probably with the participation of other still unidentified molecular events. While it is obvious that additional studies are necessary to further delineate the association between XLH and HSCR in the presence of L1CAM mutations, the documentation of this new patient reinforces the role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease.