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1.
Mol Syndromol ; 4(4): 173-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23801933

ABSTRACT

The RASA1 gene encodes p120RASGAP, a multidomain cytoplasmic protein that acts as a negative regulator of the RAS signalling pathway. Heterozygous loss-of-function RASA1 mutations were identified in patients with Parkes Weber syndrome and multifocal capillary malformations. This syndrome is characterised by a capillary blush on an extremity, arteriovenous microfistulas, and bony and soft tissue hypertrophy. The aim of this study was to test RASA1 in 2 disorders characterised by asymmetric limb enlargement and vascular malformations, namely Klippel-Trenaunay syndrome and regional capillary malformation with overgrowth. We did not identify any clear pathogenic change in these patients. Thus, besides clinical and radiological criteria, RASA1 testing constitutes an additional tool to differentiate Parkes Weber syndrome of capillary malformation-arteriovenous malformation (CM-AVM) from overlapping disorders.

2.
Diabetologia ; 48(9): 1766-75, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16025255

ABSTRACT

AIMS/HYPOTHESIS: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. SUBJECTS AND METHODS: We analysed the effect of HLA class II, insulin (INS; -23 HphI variant) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]). Those who developed beta-cell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). RESULTS: IAA emerged at a higher rate in children with the -23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. CONCLUSIONS/INTERPRETATION: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.


Subject(s)
Antibody Formation/genetics , Antigens, Differentiation/genetics , Autoimmune Diseases/genetics , Genes, MHC Class II , Islets of Langerhans/immunology , Antigens, CD , CTLA-4 Antigen , Child , Child, Preschool , Cohort Studies , Finland , HLA-DQ Antigens/genetics , HLA-DQ beta-Chains , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Infant , Insulin/genetics , Insulin Antibodies/genetics
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