HPRTSardinia: a new point mutation causing HPRT deficiency without Lesch–Nyhan disease

AbstractHypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency always causing hyperuricemia presents various degrees of neurological manifestations, the most severe which is Lesch–Nyhan syndrome. The HPRT gene is situated in the region Xq26-q27.2 and consists of 9 exons. At least 300 different mutations at different sites in the HPRT coding region from exon 1 to exon 9 have been identified. A new mutation in the HPRT gene has been determined in one patient with complete deficiency of erythrocyte activity, with hyperuricemia and gout but without Lesch–Nyhan disease. Analysis of cultured fibroblasts revealed minimal residual HPRT activity mainly when guanine was the substrate. Genomic DNA sequencing demonstrated patient's mother heterozygosity for the mutation and no mutation in her brother. The mutation consists in a C→T transversion at cDNA base 463 (C463T) in exon 6, resulting in proline to serine substitution at codon 155 (P155S). This mutation had not been reported previously and has been designated HPRTSardinia. The mutation identified in this patient allows some expression of functional enzyme in nucleated cells such as fibroblasts, indicating that such cell type may add further information to conventional blood analysis. A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency

Mapping of the Major Psoriasis-Susceptibility Locus (PSORS1) in a 70-Kb Interval around the Corneodesmosin Gene (CDSN)

Numerous putative susceptibility loci have been described for psoriasis. Among the loci confirmed in the literature, PSORS1 (the major histocompatibility complex at 6p21.3) has the strongest effect. Recent studies have highlighted a 200-kb candidate region. However, this region has not been well delimited, mainly because of the strong linkage equilibrium among the associated alleles. To finely map PSORS1, we set up a study using 17 polymorphic markers in a 525-kb interval around the human leucocyte antigen C locus (HLA-C). The results uncovered five loci with alleles strongly associated with psoriasis (Sidak-corrected P [P(c)] values from 1.8 × 10(−7) to .003), all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present on the traditional psoriasis-susceptibility extended haplotypes (HLA-Cw6-B57, HLA-Cw6-B37, and HLA-Cw6-B13) but also on a haplotype of Sardinian origin (HLA-Cw7-B58) found to be associated with psoriasis (P(c)=.0009) because of an ancestral recombination with one of the susceptibility haplotypes carrying the HLA-Cw6 allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, around the corneodesmosin (CDSN) gene

Classic Kaposi's sarcoma in Sardinia: HLA positive and negative associations

Background The incidence of classic Kaposi’s sarcoma (CKS) in northern Sardinia is one of the highest in the world. Methods Sixty-two patients with CKS were typed for class I and class II antigens. All patients had been born and were living in northern Sardinia. Results In the Sardinian patients, we observed a positive CKS association with Cw7, DRB1*1104, DRB1*1302, DQA1*0302, and DQB1*0604, and a negative CKS association with A30, B58, Cw5, DRB1*1601, and DQB1*0502. Conclusions The strong positive CKS association with DRB1*1104 and DQB1*0604 and negative association with B58 are particularly significant and further support the notion of a genetic predisposition to CKS

Association of the HLA-A2, CW2, B27, S31, DR2 Haplotype with Ankylosing Spondylitis. A Possible Role of NON-B27 Factors in the Disease

With the aim of searching for HLA haplotypes and non-B27 allele frequency variations in Sardinian AS patients, HLA-A, B, Cw, DR, DQ and Bf, C4A and C4B typing and haplotype assignment was carried out in the families of 25 AS patients and in 44 healthy individuals, all B27 heterozygotes. In the AS patients a significant increase of the A2, Cw2, B27, DR2, DQ1 haplotype was found. This depends only partially on the linkage disequilibrium existing in the Sardinian population between B27 and the other alleles of this haplotype, and rather seems to be due to a primary association of Cw2 and DR2 alleles with AS. Preliminary data seem to show that this haplotype bears the S3l complotype and the ORB1 * 1601 allele both in the AS patients and in the healthy controls. The pathogenetic implications of these findings are discussed

A Psoriasis vulgaris protective gene maps close to the HLA-C locus on the EH18.2-extended haplotype

We determined the molecular haplotypes of the HLA-A, HLA-C and HLA-B loci and the MHC class I-B-related (MIB) microsatellite in 179 unrelated psoriatic patients (72 familial cases) and in 120 controls. The HLA-A*3002-Cw*0501-B*1801-MIB1 haplotype showed a strong negative association with psoriasis vulgaris (PV) and in particular with familial PV, revealing the presence of a PV-protective gene. Analysis of association and linkage disequilibrium of the single alleles and the various two-three-four-locus segments of this haplotype indicated the presence of a protective gene telomeric to the HLA-C locus. This finding was confirmed in 13 informative multiplex PV families, in which at least one parent carried the EH18.2 haplotype. In two families, an affected sibling presented HLA-A/C recombination on the EH18.2 haplotype. A study of 12 polymorphic microsatellites in all members of the informative families, 145 PV patients, 120 controls and 32 EH18.2 homozygous healthy individuals demonstrated that the protection conferred by the EH18.2 haplotype lies within a 170 kb interval between the C143 and C244 loci, most probably in a 60 kb segment between the C132 and C244 loci