RESUMO
Hereditary pancreatitis (HP) is the second most common cause of chronic childhood pancreatitis in the United States. Mutations in the cationic trypsinogen gene on chromosome 7 are known to cause HP. We identified four families in West Virginia with symptoms consistent with HP. To determine whether members of these families had defects in the trypsinogen gene, we tested for linkage between the HP gene and simple tandem repeat markers on chromosome 7q and screened for a specific mutation in the cationic trypsinogen gene. Two-point linkage analysis indicated that the disease gene is closely linked to three 7q markers (D7S661, D7S2511, and D7S1805). Restriction fragment length polymorphism analysis showed that all clinically affected members and nonpenetrant carriers from the four families carried a G to A mutation in the third exon of the trypsinogen gene. These findings indicate that this mutation is the cause of HP in the families in our study. The observation that most individuals who carry the mutation have symptoms of HP is consistent with the high but incomplete penetrance of the trait. The presence of a single mutation and a common linked haplotype indicates that the defective allele arose in an ancestor common to all four families.
Assuntos
Mutação , Pancreatite/genética , Criança , Cromossomos Humanos Par 7/genética , Feminino , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Linhagem , Polimorfismo de Fragmento de Restrição , Tripsinogênio/genética , West VirginiaRESUMO
Human chromosomal band 11p13 has been implicated in T cell malignancies carrying t(11;14)(p13;q11) reciprocal translocations and has also been associated with Wilms' tumor and aniridia in a mechanism characterized by overlapping hemizygous constitutional deletions spanning this region. Using probes derived from the T cell receptor delta gene, we have cloned the chromosomal breakpoint in an acute T cell leukemia (T-ALL). Southern blotting analyses of mouse-human somatic cell hybrids from this human T-ALL sample and Chinese hamster-human somatic cell hybrids derived from Wilms' tumor lines have indicated that the 11p13 locus, tcl-2, juxtaposed to the TCR (T cell receptor) delta locus in T cell leukemia, is within the constitutional deletion of two Wilms' tumor-aniridia cases.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Neoplasias Renais/genética , Leucemia-Linfoma de Células T do Adulto/genética , Translocação Genética , Tumor de Wilms/genética , Animais , Mapeamento Cromossômico , Rearranjo Gênico , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T gama-deltaRESUMO
We have cloned the translocation-associated and homologous normal MYC alleles from SKW-3, a leukemia T-cell line with the t(8;14)(q24;q11) translocation, and determined the sequence of the MYC oncogene first exon and flanking 5' putative regulatory regions. S1 nuclease protection experiments utilizing a MYC first exon probe demonstrated transcriptional deregulation of the MYC gene associated with the T-cell receptor alpha locus on the 8q+ chromosome of SKW-3 cells. Nucleotide sequence analysis of the translocation-associated (8q+) MYC allele identified a single base substitution within the upstream flanking region; the homologous nontranslocated allele contained an additional substitution and a two-base deletion. None of the deletions or substitutions localized to putative 5' regulatory regions. The MYC first exon sequence was germ line in both alleles. These results demonstrate that alterations within the putative 5' MYC regulatory regions are not necessarily involved in MYC deregulation in T-cell leukemias, and they show that juxtaposition of the T-cell receptor alpha locus to a germ-line MYC oncogene results in MYC deregulation.
