Genetic Phenotypes of Alzheimer’s Disease:Mechanisms and Potential Therapy

Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease(AD).In addition to the mutations in the three main causative genes of familial AD(FAD)including presenilins and amyloid precursor protein genes,studies have identified several genes as the most plausible genes for the onset and progression of FAD,such as triggering receptor expressed on myeloid cells 2,sortilin-related receptor 1,and adenosine triphosphate-binding cassette transporter subfamily A member 7.The apolipoprotein Eε4 allele is reported to be the strongest genetic risk factor for sporadic AD(SAD),and it also plays an important role in FAD.Here,we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD.We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.

Phenotypic and genetic characterization of a novel strain of Acidithiobacillus ferrooxidans(AF2)

A comparative study on the phenotypic and genetic characteristics among Acidithiobacillus ferrooxidans （AF2）, a typic strain ATCC23270 and a previously isolated strain AF3 was performed. AF2 can use ferrous ion （Fe^2＋） or elemental sulfur （S^0） as sole energy source, but oxidizes So more effectively than Fe^2＋, which is different from ATCC23270 and AF3. The G＋C content of AF2 is 51.8% （molar fraction）, however, ATCC23270 and AF3 strains have G＋C content of 63.7% and 64.8% （molar fraction）, respectively. The DNA-DNA hybridization results show that AF2 has 41.53% and 52.38% genome similarity to ATCC 23270 and AF3, respectively, but AF3 has a high genome similarity of 89.86% to ATCC 23270 strain. Rusticyanin （rus） and subunit III of aa3-type cytochrome oxidase （coxC） genes are not detected in AF2, but Fe^2＋ oxidase （iro） gene can be detected. To understand the genomic organization of iro gene, a cosmid library of AF2 genome was constructed and iro gene-containing clone was screened. The sequencing result shows that although the nucleotide sequence of iro gene in AF2 is completely identical to that of ATCC 23270 strain, its genomic organization is different from that of ATCC 23270. In AF2, iro is located at downstream ofpurA gene, while it is located at downstream ofpetC-2 gene in ATCC 23270 strain. These results indicate that AF2 is a novel strain ofA. ferrooxidans, and that phenotypic differences among the strains ofA. ferrooxidans are closely correlated with their genetic polymorphisms.

Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome(NS)of different etiologies is critical for early clinical guidance.We employed whole-exome sequencing(WES)to detect monogenic causes of NS in a multicenter cohort of 637 patients.In this study,a genetic cause was identified in 30.0%of the idiopathic steroid-resistant nephrotic syndrome(SRNS)patients.Other than congenital nephrotic syndrome(CNS),there were no significant differences in the incidence of monogenic diseases based on the age at manifestation.Causative mutations were detected in 39.5%of patients with focal segmental glomerulosclerosis(FSGS)and 9.2%of those with minimal change disease(MCD).In terms of the patterns in patients with different types of steroid resistance,a single gene mutation was identified in 34.8%of patients with primary resistance,2.9%with secondary resistance,and 71.4%of children with multidrug resistance.Among the various intensified immunosuppressive therapies,tacrolimus(TAC)showed the highest response rate,with 49.7%of idiopathic SRNS patients achieving complete remission.Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern,and only 31.4%of patients with monogenic disease achieved a partial remission on TAC.During an average 4.1-year follow-up,21.4%of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease(ESRD).Collectively,this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients,especially those with primary and/or multidrug resistance.

Gene mutations and clinical phenotypes in Chinese children with Blau syndrome

The mutations of CARD15 gene and clinical features of Chinese patients with Blau syndrome were analyzed. We identified10 missense mutations, out of which five were new: R334 L, E383 D, R471 C, C495 R and D512 F. The rest of them, R334 W,R334Q, G481 D, M513 T and R587 C, have been reported previously. Among all the mutations, R334 W, R334 Q and C495 R had the highest frequency. Blau syndrome was found at early age after birth. It began with lepidic rash and symmetric polyarthritis and was phenotypically characterized by typical rash, arthritis, iridocyclitis and arteritis. Cardiac involvement was also found in Blau syndrome. In addition to nerve deafness, renal involvement, osteochondroma and central nervous system involvement were also found in our patients. Therefore, Chinese children with Blau syndrome have unique gene mutations and complicated clinical phenotypes. Pathologic examination and CARD15 mutation testing should be considered for diagnosis as early as possible for suspected patients.