Searching for a treatment for Alport syndrome using mouse models

Alport syndrome(AS) is a hereditary nephritis caused by mutations in COL4A3,COL4A4 or COL4A5 encoding the type IV collagen α3,α4,and α5 chains,which are major components of the glomerular basement membrane.About 20 years have passed since COL4A3,COL4A4,and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach.The phenotype of Alport mice is similar to that of Alport patients,including characteristic thickening and splitting of the glomerular basement membrane.Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies.In this review,the newer therapies for AS,such as pharmacological interventions,genetic approaches and stem cell therapies,are discussed.Although some stem cel therapies have been demonstrated to slow the rena disease progression in Alport mice,these therapies demand continual refinement as research advances.In terms of the pharmacological drugs,angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice.Novel therapies that can provide a better outcome or lead to a cure are still awaited.

Genetic polymorphisms of MC2R gene associated with responsiveness to adrenocorticotropic hormone therapy in infantile spasms

Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms （SNPs） were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs （rs1893220, rs2186944 and -2T〉C） showed a significant difference between the cases and controls （P 〈0.05 for all）. The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases （39%） than in the controls （60%） （P=-0.00003）. The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers （RR=O.42, 95%C/ 0.26-0.70, P=-0.0001）. ACTH responsiveness was strongly associated with the TCCT haplotype （P=-0.000082）. Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy （P=0.0002; P=-0.0003, respectively）. Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.