👤 Güven Lüleci

Asymptomatic Alzheimer's Disease (AsymAD) is a preclinical stage of Alzheimer's Disease (AD) identified by amyloid plaques and neurofibrillary tangles in cognitively normal individuals and offers essential understanding for early diagnosis and treatment of AD. To uncover molecular insights into AsymAD, RNA sequencing (RNA-seq) datasets from two different consortia, ROSMAP (Religious Orders Study and Memory and Aging Project) and MSBB (Mount Sinai Brain Bank), were investigated. The individuals in the datasets were grouped into AD and AsymAD based on clinical and neuropathological criteria. Differentially expressed genes (DEGs), differentially expressed transcripts (DETs), and differentially used transcripts (DUTs) were identified between AD and AsymAD samples. The results were interpreted through functional enrichment analysis and compared with the predefined lists of AD-related and learning-memory-cognition-related genes, and genes from an independent mouse dataset. The genes from the list of DEGs, DETs and DUTs were mapped onto a human protein-protein interaction network, revealing subnetworks associated with AsymAD. This led to the discovery of biomarker candidate genes: NRXN3, DGKB, ADAMTS2, GNG4, ENPP5, PCOLCE, COL25A1, COL26A1, MRPL1, and MRPL30. This study introduces an innovative approach by including DETs and DUTs in the analyses, beyond the standard focus on DEGs, pointing out comprehensive insights into the molecular mechanisms of AsymAD. In addition, combining the results of the subnetwork analysis from DEGs, DETs, and DUTs provided a new perspective to AsymAD and resulted in the discovery of further important genes, which can pave the way for early detection and intervention of AD. Show less

Bardet-Biedl syndrome (BBS) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. Patients with BBS are also at increased risk for diabetes mellitus, hypertension, and congenital heart disease. BBS is known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although these loci were all mapped on the basis of an autosomal recessive mode of inheritance, it has recently been suggested-on the basis of mutation analysis of the identified BBS2, BBS4, and BBS6 genes-that BBS displays a complex mode of inheritance in which, in some families, three mutations at two loci are necessary to manifest the disease phenotype. We recently identified BBS1, the gene most commonly involved in Bardet-Biedl syndrome. The identification of this gene allows for further evaluation of complex inheritance. In the present study we evaluate the involvement of the BBS1 gene in a cohort of 129 probands with BBS and report 10 novel BBS1 mutations. We demonstrate that a common BBS1 missense mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. We show that the BBS1 gene is highly conserved between mice and humans. Finally, we demonstrate that BBS1 is inherited in an autosomal recessive manner and is rarely, if ever, involved in complex inheritance. Show less

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance. Show less