Loss of iron homeostasis in Friedreich ataxia cells and impairment of the oxidative stress response

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin and characterized by a debilitating loss of coordination. In yeast, complete loss of frataxin causes mitochondrial iron accumulation and oxidative stress. Although FRDA cells exhibit impaired respiratory complex activity and greater sensitivity to hydrogen peroxide-induced apoptotic cell death, an increase in steady-state mitochondrial iron levels has not been conclusively shown. Pulse-chase experiments using FRDA fibroblasts suggest that severe disturbances in iron metabolism occur following supplementation with iron levels sufficient to overwhelm residual frataxin in these cells. Moreover, frataxin appears capable of forming high molecular weight complexes with iron in vitro, but the propensity of iron to nonspecifically associate with biomacromolecules complicates confirmation of this finding. Lastly, induction of oxidative stress in FRDA cells by iron loading appears unable to initiate the expected transcriptional upregulation of the antioxidant enzyme mitochondrial superoxide dismutase, possibly as a result of failed NF-kappaB activation

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

SummaryDespite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs