Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to a receptor superfamily of ligand-activated transcription factors, encoded by PPARG gene. Role of PPARγ has been well established in variety of metabolic disorders and in regulation of inflammation. In the present study, we aimed to investigate the association of PPARG (Pro12Ala; rs1801282) in clinically definite Pakistani Rheumatoid Arthritis (RA) patients and matching controls. The genotypes of the Pro12Ala variant in the PPARG were determined in a sample of 300 Pakistanis, including 150 RA cases and 150 controls. The genotyping was performed using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) method, and the data was analyzed through Graphpad Prism 5 V software. Allele-specific primer set (two forward: PPARG-F1, PPARG-F2 and a common reverse primer: PPARG-R) was used for amplification, and the product was resolved on 2 % agarose gel. The CC (ProPro) genotype has higher frequency in controls than RA cases [75 (50.0 %) vs. 51 (34.0 %)], whereas the CG (ProAla) genotype has relatively same frequencies in both cases and controls [72 (48.0 %) vs. 70 (46.6 %)]. However, significantly higher frequency of GG (AlaAla) genotype was observed in cases [27 (18.0 %) vs. 5 (3.3 %); χ2 18.54; p < 0.0001]. Furthermore, the minor allele G has significantly higher allele frequency in cases having same trend and direction of association (OR 1.991(1.412-2.808); p < 0.0001). These observations suggest that Pro12Ala (rs1801282), a coding variant in the PPARG gene, is associated with Rheumatoid Arthritis in Pakistanis.

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.

No abstract

The spectrum of rheumatic disease is wide and includes conditions with diverse pathology, although most have in common a heritable risk with a complex genetic basis. Over the past decade intense efforts have been done to understand the contribution of genotype to the expression of disease in terms of both basic pathogenesis and clinical characteristics. The dramatic improvement in technology and methodology has accelerated the pace of gene discovery in complex disorders in an exponential fashion. This review focuses on rheumatoid arthritis and describes some of the recently described genes that underlie this condition and the extent to which they overlap.