What's New at the Division of Medical Genetics of the University of Geneva Medical School

Why are our hearts are on the left side of our bodies ?

In some patients with rare genetic disorders the heart or another organ can be in the wrong position, which tells us that genes and their protein products must contribute to the normal body plan. Working on genetic material from a remarkable patient with an unusual inheritance of genes, we recently identified a gene that contributes to the laterality ("sidedness") of internal organs and which, if mutated, causes a genetic disorder called Kartagener syndrome or Primary Ciliary Dyskinesia.
The gene, known as DNAH11 (heavy chain axonemal Dynein 11), codes for one of the many proteins which compose the dynein arm, a structure involved in beating motion of cilia or flagella of cells, such as those found in the respiratory system and in spermatozoa tails. The consequences of abnormal motion of the cilia are respiratory problems, a tendancy to infections of the lung and the upper respiratory system, subnormal fertility in males, and disturbance of the usual sidedness of internal organs. The latter occurs because ciliary movements in the developing embryo help determine the position of the organs in the body (such as the heart being on the left side). This triad of symptoms defines Kartagener syndrome (which was first described by Dr Manes Kartagener, a physician in Zurich in 1933). This discovery further establishes that genes coding for the different dynein proteins are involved in ciliary function, and contribute to normal development of the embryo.

The study, which was supported financially by the Carvajal Foundation and the Swiss National Science Foundation, is published in the August 6th, 2002 issue of the prestigious international journal "Proceedings of the National Academy of Sciences, USA".

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely Primary Ciliary Dyskinesia. Lucia Bartoloni1, Jean-Louis Blouin1, Yanzhen Pan2, Corinne Gehrig1, Amit K. Maiti1, Nathalie Scamuffa1, Colette Rossier1, Mark Jorissen4, Miguel Armengot5, Maggie Meeks6, Hannah M. Mitchison6, Eddie M.K. Chung6, Celia D. Delozier-Blanchet1, William J. Craigen2,3, Stylianos E. Antonarakis1
1Division of Medical Genetics, University of Geneva Medical School, and University Hospitals, Geneva, Switzerland; 2Department of Molecular and Human Genetics, and 3Department of Pediatrics, Baylor College of Medicine, Houston, USA; 4Department of Human Genetics and Department of Ear, Nose, and Throat, University Hospital of Leuven, Leuven, Belgium; 5Otorhinolaryngology Service, General and University Hospital, Valencia, Spain; 6Department of Pediatrics and Child Health, Royal Free and University College Medical School, University College London, United Kingdom.

5 December 2002	Of mice, chromosome 21, and evolution The Human Chromosome 21 Gene Expression Atlas Non-Genic Conserved Sequences on Chromosome 21 Sequence and Analysis of the Mouse Genome
6 August 2002	Why are our hearts are on the left side of our bodies ? In some patients with rare genetic disorders the heart or another organ can be in the wrong position, which tells us that genes and their protein products must contribute to the normal body plan. Working on genetic material from a remarkable patient with an unusual inheritance of genes, we recently identified a gene that contributes to the laterality ("sidedness") of internal organs and which, if mutated, causes a genetic disorder called Kartagener syndrome or Primary Ciliary Dyskinesia. The gene, known as DNAH11 (heavy chain axonemal Dynein 11), codes for one of the many proteins which compose the dynein arm, a structure involved in beating motion of cilia or flagella of cells, such as those found in the respiratory system and in spermatozoa tails. The consequences of abnormal motion of the cilia are respiratory problems, a tendancy to infections of the lung and the upper respiratory system, subnormal fertility in males, and disturbance of the usual sidedness of internal organs. The latter occurs because ciliary movements in the developing embryo help determine the position of the organs in the body (such as the heart being on the left side). This triad of symptoms defines Kartagener syndrome (which was first described by Dr Manes Kartagener, a physician in Zurich in 1933). This discovery further establishes that genes coding for the different dynein proteins are involved in ciliary function, and contribute to normal development of the embryo. The study, which was supported financially by the Carvajal Foundation and the Swiss National Science Foundation, is published in the August 6th, 2002 issue of the prestigious international journal "Proceedings of the National Academy of Sciences, USA". Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely Primary Ciliary Dyskinesia. Lucia Bartoloni1, Jean-Louis Blouin1, Yanzhen Pan2, Corinne Gehrig1, Amit K. Maiti1, Nathalie Scamuffa1, Colette Rossier1, Mark Jorissen4, Miguel Armengot5, Maggie Meeks6, Hannah M. Mitchison6, Eddie M.K. Chung6, Celia D. Delozier-Blanchet1, William J. Craigen2,3, Stylianos E. Antonarakis1 1Division of Medical Genetics, University of Geneva Medical School, and University Hospitals, Geneva, Switzerland; 2Department of Molecular and Human Genetics, and 3Department of Pediatrics, Baylor College of Medicine, Houston, USA; 4Department of Human Genetics and Department of Ear, Nose, and Throat, University Hospital of Leuven, Leuven, Belgium; 5Otorhinolaryngology Service, General and University Hospital, Valencia, Spain; 6Department of Pediatrics and Child Health, Royal Free and University College Medical School, University College London, United Kingdom.
28 May 2000	Comprehensive chromosome 21 cSNP map ! We recently completed the first chromosome specific cSNP database and map (http://csnp.unige.ch), which covers a large proportion of chromosome 21 genes. It was generated by a combination of bioinformatics and experimental approaches. As part of our research we developed a new algorithm for automatic cSNP detection, which efficiently discriminates between low quality sequences a true variation, using the large amount of sequence data present in the public databases. We expect this tool to be useful for the analysis of complex genetic traits that map to human chromosome 21, including specific Down Syndrome phenotypes. This effort was a collaborative project between the Division of Medical Genetics of the University of Geneva Medical School and the Swiss Bioinformatics Institute in Lausanne.
18 May 2000	The sequence of human chromosome 21 is now available ! The sequence of HC21 was determined by an international consortium of scientists from Japan and Germany, and collaborating institutions in France, Switzerland, USA and UK. The paper will be published in the 18^th of May issue of Nature and is available free at http://www.nature.com/. In addition, a free copy of this issue of Nature can be obtained from http://www.nature.com/marketing/freecopy Abstract of paper The DNA sequence of human chromosome 21 M. HATTORI, A. FUJIYAMA, T. D. TAYLOR, H. WATANABE, T. YADA, H.-S. PARK, A. TOYODA, K. ISHII, Y. TOTOKI, D.-K. CHOI, E. SOEDA, M. OHKI, T. TAKAGI, Y. SAKAKI, S. TAUDIEN, K. BLECHSCHMIDT, A. POLLEY, U. MENZEL, J. DELABAR, K. KUMPF, R. LEHMANN, D. PATTERSON, K. REICHWALD, A. RUMP, M. SCHILLHABEL, A. SCHUDY, W. ZIMMERMANN, A. ROSENTHAL, J. KUDOH, K. SHIBUYA, K. KAWASAKI, S. ASAKAWA, A. SHINTANI, T. SASAKI, K. NAGAMINE, S. MITSUYAMA, S. E. ANTONARAKIS, S. MINOSHIMA, N. SHIMIZU, G. NORDSIEK, K. HORNISCHER, P. BRANDT, M. SCHARFE, O. SCHÖN, A. DESARIO, J. REICHELT, G. KAUER, H. BLÖCKER, J. RAMSER, A. BECK, S. KLAGES, S. HENNIG, L. RIESSELMANN, E. DAGAND, S. WEHRMEYER, K. BORZYM, K. GARDINER, D. NIZETIC, F. FRANCIS, H. LEHRACH, R. REINHARDT & M.-L. YASPO Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1 in 700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumours. Here we report the sequence and gene catalogue of the long arm of chromosome 21. We have sequenced 33,546,361 basepairs (bp) of DNA with very high accuracy, the largest contig being 25,491,867 bp. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 kilobases. Thus, we achieved 99.7% coverage of 21q. We also sequenced 281,116 bp from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes and 59 pseudogenes. The sequence data can be obtained from http://hgp.gsc.riken.go.jp/chr21/index.html Links to home pages of groups involved RIKEN, Genomic Sciences Center, Sagamihara 228-8555, Japan http://hgp.gsc.riken.go.jp/ Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan http://adenine.dmb.med.keio.ac.jp/ Institut für Molekulare Biotechnologie, Genomanalyse, D-07745 Jena, Germany http://genome.imb-jena.de/ Max-Planck-Institut für Molekulare Genetik, D-14195 Berlin-Dahlem, Germany http://chr21.rz-berlin.mpg.de/ GBF (German Research Centre for Biotechnology), Genome Analysis, D-38124 Braunschweig, Germany http://www.genome.gbf.de/