ABSTRACT
The bovine and ovine TRG genes have previously been shown to be located in two loci, TRG1 and TRG2, in contrast to human and mouse TRG genes that are located in a single locus. The bovine TRG1 and TRG2 loci are located on chromosome 4 at 4q3.1 and 4q1.5-2.2, respectively. The complete genomic organization of the two bovine loci is described: each locus comprises three cassettes, each one includes one or several variable genes (TRGV) and one or several joining genes (TRGJ) preceding a constant (TRGC) gene. The location of the TRGC5 cassette is conclusively described in 5' of the TRG1 locus. Analysis of 17 TRGV belonging to 10 different subgroups, 8 TRGJ and 6 TRGC genes is conducted which comprises the most comprehensive list to date.
Subject(s)
Cattle/genetics , Genes, T-Cell Receptor gamma/genetics , Genome/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosomes, Artificial, Bacterial/genetics , DNA/chemistry , DNA/genetics , Gene Library , Molecular Sequence Data , Phylogeny , Sequence Alignment , Sequence Analysis, DNAABSTRACT
BACKGROUND: von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which affected individuals may develop CNS and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, and cysts of various organs. The VHL gene has been localized to chromosome 3p25-26 and >500 germline mutations have been identified. A rare variant of the VHL gene results in the substitution of lysine for proline at position 25 (P25L) in the larger of the two VHL proteins. This VHL variant has previously been described in a limited number of cases and has been strongly suggested to be non-pathogenic, but this has not been proven. METHODS: A family with a medical history suggestive of VHL disease was investigated using DNA sequence analysis to determine the presence of the P25L variant of the VHL protein. RESULTS: Sequence analysis identified the VHL P25L variant in 7 of 14 family members, one of whom had a single retinal hemangioma, which is in itself insufficient to diagnose VHL disease. The variant was not identified in a family member with clear cell renal carcinoma, which is a hallmark feature of VHL disease. CONCLUSIONS: On the basis of these results, it is concluded that P25L is a benign variant of the VHL protein and individuals carrying this variant should not be required to undergo screening for VHL manifestations.
Subject(s)
Amino Acid Substitution , Von Hippel-Lindau Tumor Suppressor Protein/genetics , von Hippel-Lindau Disease/genetics , Aged , Humans , Lysine/chemistry , Lysine/genetics , Middle Aged , Mutation , Pedigree , Proline/chemistry , Proline/genetics , von Hippel-Lindau Disease/pathologyABSTRACT
Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.
