A novel EFNB1 mutation in a patient with craniofrontonasal syndrome and right hallux duplication.

Craniofrontonasal syndrome (CFNS, MIM #304110) is a rare X-linked dominant developmental disorder that shows paradoxically greater severity in affected females than in affected males. Our female patient with frontonasal dysplasia, craniosynostosis and additional malformations was consistent with CFNS. EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases, is the only gene in which mutation is known to cause CFNS. Here, we describe 402T>C, a novel de novo mutation on EFNB1. This mutation results in substitution of highly conserved isoleucine at 134th residue to threonine.

Rheumatoid arthritis risk associates with DNA repair gene XRCC1 Arg399Gln polymorphism in Turkish patients.

Rheumatoid arthritis (RA) is an autoinflammatory disease with a genetic background. The synoviocytes in RA shows cellular transformation with tumor-like features, and RA patients have genomic instability and relaxation of DNA repair mechanisms. The polymorphisms in BER repair pathway genes, XRCC1 and OGG1, may change the response to inflammation via altered DNA repair capacity. In this study, we aimed to investigate the relationship between the risk of RA and XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms in a group of Turkish RA patients. XRCC1 Arg194Trp, Arg399Gln, and OGG1 Ser326Cys polymorphisms were investigated by PCR-RFLP method in 100 RA patients and 158 healthy control subjects. The results were statistically analyzed by calculating the odds ratios (OR) and their 95% confidence intervals (95% CI) using the χ(2)-tests. RA patients in this study had significantly higher frequencies of XRCC1 Arg399Gln polymorphism in both homozygote (GG) (35%, OR: 7.78 [95% CI: 3.65-16.59], P < 0.001) and heterozygote (AG) forms (41%, OR: 2.17 [95% CI: 1.19-3.96], P < 0.01) and also increased frequency of 399Gln (G) allele (55%, OR:2.99 [95% CI: 1.67-5.37], P < 0.001). We conclude that XRCC1 Arg194Trp, and OGG1 Ser326Cys polymorphisms are not associated with RA; however, Arg399Gln polymorphism is a significant risk factor of RA, and carriers of 399Gln (G) allele have greater risk of RA.

Glioma risk associates with polymorphisms of DNA repair genes, XRCC1 and PARP1.

Cancer develops through interactions between polygenic and environmental factors, and changes in DNA repair pathway can increase susceptibility to tumours. XRCC1 and PARP1 are two proteins that act cooperatively in base excision repair (BER) of DNA. The polymorphisms of genes coding these proteins may effect their action in BER pathway. In this study, we aimed to investigate the associations between glioma risk and XRCC1 Arg399Gln and PARP1 Val762Ala polymorphisms per se and in combination. XRCC1 Arg399Gln and PARP1 Val726Ala polymorphisms were investigated by PCR-RFLP method in 119 glioma patients and 180 cancer-free control subjects. The results were statistically analysed by calculating the odds ratios (OR) and their 95% confidence intervals (95% CI) using the χ2 tests. Glioma patients in this study had significantly higher frequencies of XRCC1 Arg399Gln polymorphism both in homozygote (GG) and heterozygote (AG) status (31% and 56%, respectively) (p < 0.001), and also increased frequency of 399Gln (G) allele (59%) (p < 0.001). Val/Ala (VA) genotype of PARP1 Val762Ala polymorphism was significantly more in the control group (p = 0.02). The combined genotypes of XRCC1 AG or GG with PARP1 VA or AA, and XRCC1 AG or GG with PARP1 VV were more represented in the glioma patients (p = 0.001 and 0.003, respectively). We conclude that XRCC1 Arg399Gln polymorphism is a significant risk factor, and 399Gln (G) allele carries a 3.5 times greater risk for glioma, while PARP1 Val/Ala genotype may be protective against it. We also suspect that in the presence of a polymorphic (G) allele of XRCC1, the plausible protective effect of PARP1 VA genotype may be greatly suppressed.

Marked improvement in Segawa syndrome after L-dopa and selegiline treatment.

Three brothers, born to parents who were first cousins, were referred for progressive diffuse dystonia. Initial physical examinations revealed minor dysmorphic features, e.g., bifrontal narrowing, downslanting palpebral fissures, low-set ears, upturned nostrils, and microretrognathia, as well as neurodevelopmental delay. Absence of eye contact and head control, diffuse dystonia, hypokinesia, choreoathetosis, tremor, increased deep tendon reflexes, diffuse muscle atrophy, and spasticity were evident during neurologic evaluations. After laboratory investigations, imaging studies, and the exclusion of other causes of childhood dystonia, the children were diagnosed with Segawa syndrome. A molecular analysis of the tyrosine hydroxylase gene revealed a novel P492R (1475 C>G) mutation, further confirming the clinical diagnosis. After 1-month therapy with 2 mg/kg/day l-dopa, no changes in signs were evident. Selegiline was added, which greatly improved the clinical picture. Segawa syndrome in three brothers resulted from a novel mutation in the tyrosine hydroxylase gene. Treatment with a combination of l-dopa and selegiline led to favorable outcomes.