Dataset Information

Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

ABSTRACT: Mutations in GBA1 gene result in defective acid ?-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at P value 1.26 × 10(-6) . Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients, in whom CLN8 risk alleles were overrepresented. In an in vitro cell model of GD, CLN8 expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.

SUBMITTER: Zhang CK

PROVIDER: S-EPMC3684025 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

Zhang Clarence K CK Stein Philip B PB Liu Jun J Wang Zuoheng Z Yang Ruhua R Cho Judy H JH Gregersen Peter K PK Aerts Johannes M F G JM Zhao Hongyu H Pastores Gregory M GM Mistry Pramod K PK

American journal of hematology 20120303 4

Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or sever ...[more]

PMID: 22388998

Similar Datasets

Project description:HYPOTHESIS:Clinical adult cochlear implant (CI) candidacy evaluations rely heavily on measures of sentence recognition under the best-aided listening conditions. The hypothesis tested in this study was that nonauditory measures of neurocognitive processes would contribute to scores on preoperative sentence recognition for CI candidates, above and beyond hearing ability as assessed using pure-tone average (PTA). Support for this hypothesis would suggest that best-aided sentence recognition is not simply a measure of hearing ability; rather, neurocognitive functions contribute to performance and should be considered while counseling patients during CI candidacy evaluation about postoperative rehabilitative and outcome expectations. BACKGROUND:Neurocognitive functions, such as working memory capacity, inhibition-concentration, information processing speed, and nonverbal reasoning contribute to aided speech recognition outcomes in adults with hearing loss. This study examined the roles of these neurocognitive factors on preoperative speech recognition performance in adults evaluated for CI candidacy. METHODS:Thirty-one postlingually deafened adult CI candidates were enrolled. Participants were assessed using nonauditory measures of working memory capacity, inhibition-concentration, information processing speed, and nonverbal reasoning. Measures of sentence recognition in quiet and in multitalker babble (AzBio sentences) as well as sentences from the City University of New York in quiet were collected under best-aided conditions. RESULTS:AzBio sentence recognition scores in babble were predicted significantly by scores of working memory capacity after accounting for PTA. Similarly, the City University of New York sentence recognition scores were predicted significantly by nonverbal reasoning after accounting for PTA. CONCLUSIONS:Findings support the idea that clinical measures of sentence recognition may be affected to varying degrees by neurocognitive functions, and these functions should be considered during evaluation for CI candidacy.

Project description:Background and aimsPhenotypic variability is a successful strategy in lichens for colonizing different habitats. Vagrancy has been reported as a specific adaptation for lichens living in steppe habitats around the world. Among the facultatively vagrant species, the cosmopolitan Cetraria aculeata apparently forms extremely modified vagrant thalli in steppe habitats of Central Spain. The aim of this study was to investigate whether these changes are phenotypic plasticity (a single genotype producing different phenotypes), by characterizing the anatomical and ultrastructural changes observed in vagrant morphs, and measuring differences in ecophysiological performance.MethodsSpecimens of vagrant and attached populations of C. aculeata were collected on the steppes of Central Spain. The fungal internal transcribed spacer (ITS), glyceraldehyde-3-phosphate dehydrogenase (GPD) and the large sub-unit of the mitochondrial ribosomal DNA (mtLSUm), and the algal ITS and actin were studied within a population genetics framework. Semi-thin and ultrathin sections were analysed by means of optical, scanning electron and transmission electron microscopy. Gas exchange and chlorophyll fluorescence were used to compare the physiological performance of both morphs.Key results and conclusionsVagrant and attached morphs share multilocus haplotypes which may indicate that they belong to the same species in spite of their completely different anatomy. However, differentiation tests suggested that vagrant specimens do not represent a random sub-set of the surrounding population. The morphological differences were related to anatomical and ultrastructural differences. Large intercalary growth rates of thalli after the loss of the basal-apical thallus polarity may be the cause of the increased growth shown by vagrant specimens. The anatomical and morphological changes lead to greater duration of ecophysiological activity in vagrant specimens. Although the anatomical and physiological changes could be chance effects, the genetic differentiation between vagrant and attached sub-populations and the higher biomass of the former show fitness effects and adaptation to dry environmental conditions in steppe habitats.

Dataset Information

Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

Publications

Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets