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      Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

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          Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth.

          Author Summary

          Inherited hypertrichoses represent a group of hair overgrowth syndromes that are extremely rare in humans and have remained an area of great interest to evolutionary geneticists since they are considered to be recurrences of an ancestral phenotype. These syndromes often present with additional congenital abnormalities including bone, heart and dental defects; thus, it is crucial to identify the mechanisms and genes underlying the pathology. Copy number variants (CNVs) have previously been reported in several cases of congenital generalized hypertrichosis terminalis (CGHT) with a minimal overlapping region of 555 kb encompassing four genes. However, no point mutations in these or any other single genes have been described to underlie the CGHT phenotype. In this study, we report the first loss-of-function mutation in an ABC transporter, ABCA5 and identified an additional copy number variant in a separate case that lies within the minimal common region. We found high levels of ABCA5 expression in both epithelial and mesenchymal compartments of human and mouse hair follicles, and in CGHT patients, this expression is significantly reduced or completely lost. ABCA5 is a lysosomal protein, and its loss-of-function compromises the integrity of lysosomes and leads to an intra-endolysosomal accumulation of cholesterol. Importantly, our findings support a novel role for ABCA5 in regulating hair growth.

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          Most cited references 55

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            ESEfinder: A web resource to identify exonic splicing enhancers.

             L Cartegni (2003)
            Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder ( is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.
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              Improved splice site detection in Genie.

              We present an improved splice site predictor for the genefinding program Genie. Genie is based on a generalized Hidden Markov Model (GHMM) that describes the grammar of a legal parse of a multi-exon gene in a DNA sequence. In Genie, probabilities are estimated for gene features by using dynamic programming to combine information from multiple content and signal sensors, including sensors that integrate matches to homologous sequences from a database. One of the hardest problems in genefinding is to determine the complete gene structure correctly. The splice site sensors are the key signal sensors that address this problem. We replaced the existing splice site sensors in Genie with two novel neural networks based on dinucleotide frequencies. Using these novel sensors, Genie shows significant improvements in the sensitivity and specificity of gene structure identification. Experimental results in tests using a standard set of annotated genes showed that Genie identified 86% of coding nucleotides correctly with a specificity of 85%, versus 80% and 84% in the older system. In further splice site experiments, we also looked at correlations between splice site scores and intron and exon lengths, as well as at the effect of distance to the nearest splice site on false positive rates.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                May 2014
                15 May 2014
                : 10
                : 5
                [1 ]Department of Genetics and Development, Columbia University, New York, New York, United States of America
                [2 ]Department of Dermatology, Columbia University, New York, New York, United States of America
                [3 ]Department of Pediatrics, Columbia University Medical Center, New York, New York, United States of America
                [4 ]Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America
                [5 ]Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, United States of America
                [6 ]St. Luke's-Roosevelt Hospital Center, New York, New York, United States of America
                [7 ]Centro Dermatológico Pascua, Mexico City, Mexico
                [8 ]New York Presbyterian Hospital, New York, New York, United States of America
                [9 ]Basic Science, Universidad de Monterrey, Nueva Leon, Mexico
                Max-Delbrück-Center for Molecular Medicine, Germany
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GMD AMC. Performed the experiments: GMD. Analyzed the data: GMD CD GDP. Contributed reagents/materials/analysis tools: CD GDP. Wrote the paper: GMD. Performed autophagy analysis and filipin staining: CD. Performed experiments and analyses in sporadic CGHT case: GMD MKu VJ KAF MKi MTS AS AV DW BL. Performed clinical evaluations of the patients and provided clinical photos: KAY HF NS LR LDLC JCSA.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 15
                This work was supported by NIH/NIAMS Grant P30AR44535 ( GMD was supported by Columbia University Department of Genetics and Development Training Grant (T32GM007088) and is now supported by an F31 fellowship (NIH/NIDCR; F31 DE023472-01A1). This work was supported in part by the Skin Disease Research Center in the Department of Dermatology at Columbia University (USPHS P3044345) and the NIH/NIAMS Grant R01AR44924 (to AMC). ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Genetic Engineering
                Gene Expression
                Genetics of Disease
                Human Genetics
                Molecular Genetics



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