Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio (‘desaturation index’) – displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = −0.80; P = 0.0001) and the Boston Naming test (r = −0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance

The genetics of familial combined hyperlipidaemia.

Item does not contain fulltextAlmost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes.1 juni 201