RESUMEN
Germ-line mutations of the RET proto-oncogene, involving five cysteine residues at codons 609, 611, 618, 620 and 634, are associated with two variants of the inherited cancer syndrome multiple endocrine neoplasia type 2: type 2A and familial medullary thyroid carcinoma. The association of multiple endocrine neoplasia type 2A with the dermatological disorder cutaneous lichen amyloidosis has already been reported, and mutations in the Cys634 have been identified in different families. We describe here an additional pedigree in which multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis cosegregate. A Cys634Gly was identified by direct sequencing of the RET proto-oncogene exon 11 in the affected individuals. The mutation creates a new HaeIII site, and restriction analysis performed on all family members rules out the presence of the altered allele in two children and consequently the risk of developing thyroid tumors. These results emphasize the role of molecular analysis of the RET proto-oncogene in diagnosing presymptomatically those individuals at risk of inheriting the disease allele.
Asunto(s)
Amiloidosis/genética , Proteínas de Drosophila , Erupciones Liquenoides/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Adolescente , Adulto , Amiloidosis/diagnóstico , Niño , Cisteína/genética , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Femenino , Glicina/genética , Humanos , Erupciones Liquenoides/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Linaje , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/metabolismo , Análisis de Secuencia de ADNRESUMEN
HOX11L1 is a homeobox gene involved in peripheral nervous system development as confirmed by knockout mice exhibiting megacolon with enteric ganglia, a phenotype associated in human with Intestinal Neuronal Dysplasia (IND). Using FISH and radiation hybrids we have localized HOX11L1 to human chromosome 2p13.1-->p12, in a 14-cR interval between WI-5987 (D2S2088) and GCT1B4 (D2S2497), and confirmed the synteny between mouse 6C3-D1 and human 2p13.1-->p12 chromosomes by mapping an EST cDNA clone corresponding to mouse HOX11L1 (Tlx2).
Asunto(s)
Cromosomas Humanos Par 2/genética , Genes Homeobox , Ratones/genética , Animales , Secuencia de Bases , Bandeo Cromosómico , Mapeo Cromosómico , Cartilla de ADN/genética , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Intestinos/inervación , Intestinos/patología , Ratones Noqueados , Fenotipo , Especificidad de la EspecieRESUMEN
In a few patients with Hirschsprung disease (HSCR) and no clinical symptoms of multiple endocrine neoplasia type 2 (MEN-2A) or medullary thyroid carcinoma (MTC), missense mutations in the cysteine residues 609 and 620 of the Ret gene have been identified. In several pedigrees with either MEN-2A or familial MTC (FMTC) a documented germline mutation in cysteine 618 or 620 follows the segregation of the disease phenotype. The appearance of the HSCR phenotype in such patients and pedigrees cannot be easily reconciled with the gain of function which is associated with the dominant oncogenic effect of MEN-2A mutations. Gastrointestinal manifestations are known to occur also in association with MEN-2B but, to the best of our knowledge, in only very few cases the intestinal phenotype of MEN-2B has been investigated by enzymo-histochemical techniques, as in the present work. We report an extensive molecular study of patients, two with HSCR and FMTC carrying a Cys620Arg or Ser mutation and two with MEN-2B and gastrointestinal symptoms carrying a Met918Thr mutation. One of the latter two patients showed aganglionosis of the last 5 cm of rectum which caused a congenital megacolon leading to the diagnosis and operation for HSCR. The mutation screening of all the exons of Ret in 3 of these patients did not reveal any additional mutation. Therefore these results do not support the hypothesis of additional constitutional Ret mutations in patients showing association of MEN-2 and HSCR, whilst the histochemical and clinical data in one of these patients indicate that MEN-2B can be associated with a true form of short segment HSCR.