IFRD1 is a candidate gene for SMNA on chromosome 7q22–q23

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98104, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2009; 84(5):692-7. DOI: 10.1016/j.ajhg.2009.04.008
Source: PubMed


We have established strong linkage evidence that supports mapping autosomal-dominant sensory/motor neuropathy with ataxia (SMNA) to chromosome 7q22-q32. SMNA is a rare neurological disorder whose phenotype encompasses both the central and the peripheral nervous system. In order to identify a gene responsible for SMNA, we have undertaken a comprehensive genomic evaluation of the region of linkage, including evaluation for repeat expansion and small deletions or duplications, capillary sequencing of candidate genes, and massively parallel sequencing of all coding exons. We excluded repeat expansion and small deletions or duplications as causative, and through microarray-based hybrid capture and massively parallel short-read sequencing, we identified a nonsynonymous variant in the human interferon-related developmental regulator gene 1 (IFRD1) as a disease-causing candidate. Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA. Mutation analysis of IFRD1 in additional patients with similar phenotypes is needed for demonstration of causality and further evaluation of its importance in neurological diseases.

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Available from: Wendy H Raskind, Apr 26, 2014
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    • "The significant MO and FC signals identified here implicate regions containing promising candidate genes that warrant further exploration by targeted re-sequencing (for example, [66-69]). The MO peak at 1p31.3 is located directly over NFIA [GenBank:NG_011787], whose gene product has transcription factor activity and has been implicated in central nervous system development [55,56]. "
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    ABSTRACT: Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE. From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds >=2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions. We observed an independent replication of previously observed linkage at chromosome 20p13 (P < 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions. With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk.
    Molecular Autism 02/2014; 5(1):13. DOI:10.1186/2040-2392-5-13 · 5.41 Impact Factor
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    • "to numbers of growth factors such as epidermal growth factor and nerve growth factor in vitro [9]. Although IFRD1 modulates the pathophysiology of human cystic fibrosis lung disease through regulation of the neutrophil effector function [10], IFRD1 is a candidate gene for autosomal-dominant sensory/motor neuropathy with ataxia, which is a rare neurological disorder whose phenotype involves both the central and peripheral nervous systems in humans [11]. Accordingly, TIS7 has been implicated in the regulation of cell growth and differentiation, in addition to the pathogenesis of various diseases, through modulating patterns of gene expression. "
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    ABSTRACT: Although tetradecanoyl phorbol acetate induced sequence-7 (TIS7) has been identified as a co-activator/repressor of gene transcription in different eukaryotic cells, little attention has been paid to the functionality of TIS7 in adipocytes. Here, we evaluated the possible role of TIS7 in mechanisms underlying the regulation of adipogenesis. TIS7 expression was preferentially up-regulated in white adipose tissues (WAT) of obesity model mice as well as in pre-adipocytic 3T3-L1 cells cultured under hypoxic conditions. TIS7 promoter activity was selectively enhanced by activating transcription factor-6 (ATF6) among different transcription factors tested, while induction of TIS7 by hypoxic stress was markedly prevented by knockdown of ATF6 by shRNA in 3T3-L1 cells. Overexpression of TIS7 markedly inhibited Oil Red O staining and expression of particular adipogenic genes in 3T3-L1 cells. TIS7 synergistically promoted gene transactivation mediated by Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin, while blockade of the Wnt/β-catenin pathway by a dominant negative form of T-cell factor-4 (DN-TCF4) markedly prevented the inhibition of adipogenesis in 3T3-L1 cells with TIS7 overexpression. TIS7 predominantly interacted with β-catenin in the nucleus of WAT in the genetically obese ob/ob mice as well as in 3T3-L1 cells cultured under hypoxic conditions. Both knockdown of TIS7 by shRNA and introduction of DN-TCF4 similarly reversed the hypoxia-induced inhibition of adipogenic gene expression in 3T3-L1 cells. These findings suggest that TIS7 could play a pivotal role in adipogenesis through interacting with β-catenin to promote the canonical Wnt signaling in pre-adipocytes under hypoxic stress such as obesity.
    Biochimica et Biophysica Acta 03/2013; 1832(8). DOI:10.1016/j.bbadis.2013.03.010 · 4.66 Impact Factor
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    • "High-throughput sequencing (HTS) has emerged as a powerful tool to study undiagnosed diseases. Many recent publications describe new genes discovered by whole exome sequencing [Bilguvar et al., 2010; Bonnefond et al., 2010; Choi et al., 2009; Erlich et al., 2011; Hoischen et al., 2010; Kalay et al., 2011; Klein et al., 2011; Krawitz et al., 2010; Lalonde et al., 2010; Ng et al., 2010a; Ng et al., 2010b; Puente et al., 2011; Simpson et al., 2011; Sobreira et al., 2010; Walsh et al., 2010; Wei et al., 2011; Worthey et al., 2011], and additional publications report genes identified by related techniques [Brkanac et al., 2009; Johnston et al., 2010; Kahrizi et al., 2011; Lupski et al., 2010; Nikopoulos et al., 2010; Rehman et al., 2010; Rios et al., 2010; Summerer et al., 2010; Volpi et al., 2010]. HTS methods produce a list of genotype calls numbering on the order of 10 4 per exome, 10 5 for the combined exomes of a small family, and 10 6 per genome. "
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    ABSTRACT: The Undiagnosed Diseases Program at the National Institutes of Health uses high-throughput sequencing (HTS) to diagnose rare and novel diseases. HTS techniques generate large numbers of DNA sequence variants, which must be analyzed and filtered to find candidates for disease causation. Despite the publication of an increasing number of successful exome-based projects, there has been little formal discussion of the analytic steps applied to HTS variant lists. We present the results of our experience with over 30 families for whom HTS sequencing was used in an attempt to find clinical diagnoses. For each family, exome sequence was augmented with high-density SNP-array data. We present a discussion of the theory and practical application of each analytic step and provide example data to illustrate our approach. The article is designed to provide an analytic roadmap for variant analysis, thereby enabling a wide range of researchers and clinical genetics practitioners to perform direct analysis of HTS data for their patients and projects. Hum Mutat 33:599–608, 2012. © 2012 Wiley Periodicals, Inc. †
    Human Mutation 04/2012; 33(4):599-608. DOI:10.1002/humu.22035 · 5.14 Impact Factor
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