Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1114-1121, 24 April 2008
doi:10.1016/j.ajhg.2008.03.014
Article
Alopecia, Neurological Defects, and Endocrinopathy Syndrome Caused by Decreased Expression of RBM28, a Nucleolar Protein Associated with Ribosome Biogenesis
Janna Nousbeck1, 2, 3, 11, Ronen Spiegel3, 6, 11, Akemi Ishida-Yamamoto8, Margarita Indelman1, Ayelet Shani-Adir7, Noam Adir4, Ehud Lipkin2, 3, Sivan Bercovici5, Dan Geiger5, Maurice A. van Steensel9, Peter M. Steijlen9, Reuven Bergman1, 3, Albrecht Bindereif10, Mordechai Choder3, Stavit Shalev3, 6 and Eli Sprecher1, 2, 3, 
, 
1 Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Health Care Campus, 31096 Haifa, Israel
2 Center for Translational Genetics, Rappaport Institute for Research in the Medical Sciences, Technion—Israel Institute of Technology, 31096 Haifa, Israel
3 Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, 31096 Haifa, Israel
4 Schulich Faculty of Chemistry, Technion—Israel Institute of Technology, 31096 Haifa, Israel
5 Computer Science Department, Technion—Israel Institute of Technology, 31096 Haifa, Israel
6 Genetic Institute, Ha'emek Medical Center, 18101 Afula, Israel
7 Department of Dermatology, Ha'emek Medical Center, 18101 Afula, Israel
8 Department of Dermatology, Asahikawa Medical College, 078-8510 Asahikawa, Japan
9 Department of Dermatology, University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands
10 Institute of Biochemistry, Department of Biology and Chemistry, Justus-Liebig-University of Giessen, 35390 Giessen, Germany
Corresponding author11 These authors contributed equally to this work.
Abstract
Single-gene disorders offer unique opportunities to shed light upon fundamental physiological processes in humans. We investigated an autosomal-recessive phenotype characterized by alopecia, progressive neurological defects, and endocrinopathy (ANE syndrome). By using homozygosity mapping and candidate-gene analysis, we identified a loss-of-function mutation in RBM28, encoding a nucleolar protein. RBM28 yeast ortholog, Nop4p, was previously found to regulate ribosome biogenesis. Accordingly, electron microscopy revealed marked ribosome depletion and structural abnormalities of the rough endoplasmic reticulum in patient cells, ascribing ANE syndrome to the restricted group of inherited disorders associated with ribosomal dysfunction.
Article Information
PubMed
Related Articles
- A Gene for Universal Congenital Alopecia Maps to Chromosome ...A Gene for Universal Congenital Alopecia Maps to Chromosome 8p21-22
The American Journal of Human Genetics, Volume 62, Issue 2, 1 February 1998, Pages 386-390
Markus M. Nöthen, Sven Cichon, Ina R. Vogt, Susanne Hemmer, Roland Kruse, Michael Knapp, Tobias Höller, Muhammad Faiyaz ul Haque, Sayedul Haque, Peter Propping, Mahmud Ahmad and Marcella Rietschel
AbstractSummary: Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.
Abstract | | - A Gene for Hypotrichosis Simplex of the Scalp Maps to Chromo...A Gene for Hypotrichosis Simplex of the Scalp Maps to Chromosome 6p21.3
The American Journal of Human Genetics, Volume 66, Issue 6, 1 June 2000, Pages 1979-1983
Regina C. Betz, Young-Ae Lee, Anette Bygum, Flemming Brandrup, Ana I. Bernal, Jaime Toribio, J. Ignacio Alvarez, Guido M. Kukuk, Hans Henning W. Ibsen, Hanne B. Rasmussen, Thomas F. Wienker, André Reis, Peter Propping, Roland Kruse, Sven Cichon and Markus M. Nöthen
AbstractHypotrichosis simplex of the scalp (HSS) is an autosomal dominant form of isolated alopecia causing almost complete loss of scalp hair, with onset in childhood. After exclusion of candidate regions previously associated with hair-loss disorders, we performed a genomewide linkage analysis in two Danish families and localized the gene to chromosome 6p21.3. This was confirmed in a Spanish family, with a total LOD score of 11.97 for marker D6S1701 in all families. The combined haplotype data identify a critical interval of 14.9 cM between markers D6S276 and D6S1607. Localization of the locus for HSS to 6p21.3 is a first step toward identification of the gene. The gene will give important insights into the molecular and cellular basis of hair growth on the scalp.
Abstract | | - Identification of a Genetic Defect in the Hairless Gene in A...Identification of a Genetic Defect in the Hairless Gene in Atrichia with Papular Lesions: Evidence for Phenotypic Heterogeneity among Inherited Atrichias
The American Journal of Human Genetics, Volume 64, Issue 5, 1 May 1999, Pages 1323-1329
Eli Sprecher, Reuven Bergman, Raymonde Szargel, Rachel Friedman-Birnbaum and Nadine Cohen
AbstractSummary: Recently, we showed that atrichia with papular lesions (APL), a rare inherited form of alopecia, is transmitted as an autosomal recessive trait in a large inbred kindred of Israeli-Arab origin. Furthermore, we mapped the APL locus to a 5-cM region of chromosome 8p12 in this family. The human “hairless” gene is a candidate target gene for the disease mutation because it maps to the APL locus and because it was recently found to be mutated in a related but clinically distinct form of alopecia known as “alopecia universalis” or “congenital alopecia.” In the present study, the coding sequence of the hairless gene was compared by reverse transcription–PCR in fibroblast cell lines derived from an affected patient and an unrelated individual. We identified a single-base deletion (3434delC) in the hairless gene that cosegregated with the disease phenotype in the family. This deletion is predicted to cause a frameshift mutation in the highly conserved C-terminal part of the hairless protein, a region putatively involved in the transcription factor activity of the hairless gene product. The present results are indicative of phenotypic heterogeneity in inherited atrichias caused by mutations in the hairless gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development.
Abstract | | - …more
