C21orf5, a new member of Dopey family involved in morphogenesis, could participate in neurological alterations and mental retardation in Down syndrome.

Availability of the human genome sequence promises important progress in the understanding of human pathologies, particularly for multifactorial diseases. Among these, Down syndrome (DS) is the most frequent genetic cause of mental retardation. A critical region of chromosome 21, the Down syndrome Chromosomal Region-1 (DCR-1), is responsible for many features of the DS phenotype including mental retardation. We studied DCR-1 C21orf5 as a new candidate gene for DS considering its restricted expression in key brain regions altered in DS patients and involved in learning and memory processes. To elucidate C21orf5 molecular function, we performed a comparative study of protein sequences in several species and showed that C21orf5 represents a new member of the Dopey leucine zipper-like family. The C21orf5 C-termini contains two highly conserved leucine-like zipper domains in invertebrate and vertebrate species. Evolution analysis indicated a common ancestral origin of these protein sequences also suggesting a conserved function of this gene throughout phylogenesis. Mutations of the known C21orf5 homologous genes Aspergillus nidulans DopA, Saccharomyces cerevisiae Dop1 and Caenorhabditis elegans pad1, determine morphological abnormalities. We studied transgenic mice carrying the human C21orf5 gene and we showed that this gene is overexpressed in brain regions by in situ hybridization and by real-time RT-PCR experiments. Interestingly, we also showed that these transgenic mice have an increased density of cortical cells overexpressing C21orf5. Similarly, DS patients have an altered lamination pattern in their cortex. Considering together our and previous findings, we suggest that the human dopey family member, C21orf5, could play a role in brain morphogenesis and, when overexpressed, it could participate in neurological features and mental retardation observed in DS patients.

[1]  Jan-Fang Cheng,et al.  Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome , 1997, Nature Genetics.

[2]  J M Delabar,et al.  Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Matise,et al.  Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. , 1994, Human molecular genetics.

[4]  X. Estivill,et al.  Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. , 2001, Human molecular genetics.

[5]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[6]  B. Dujon.  The yeast genome project: what did we learn? , 1996, Trends in genetics : TIG.

[7]  B. Miller,et al.  Morphogenesis in Aspergillus nidulans requires Dopey (DopA), a member of a novel family of leucine zipper‐like proteins conserved from yeast to humans , 2000, Molecular microbiology.

[8]  S. P. Fodor,et al.  Large-Scale Transcriptional Activity in Chromosomes 21 and 22 , 2002, Science.

[9]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[10]  B T Hyman,et al.  Development of the Superior Temporal Neocortex Is Anomalous in Trisomy 21 , 1994, Journal of neuropathology and experimental neurology.

[11]  N. Cairns,et al.  Excitatory amino acids and monoamines in parahippocampal gyrus and frontal cortical pole of adults with Down syndrome. , 1997, Life sciences.

[12]  E. Kandel,et al.  Cognitive Neuroscience and the Study of Memory , 1998, Neuron.

[13]  G Deléage,et al.  An algorithm for protein secondary structure prediction based on class prediction. , 1987, Protein engineering.

[14]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[15]  S. Antonarakis,et al.  C21orf5, a novel human chromosome 21 gene, has a Caenorhabditis elegans ortholog (pad-1) required for embryonic patterning. , 2000, Genomics.

[16]  S. Antonarakis,et al.  Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome. , 1998, Genomics.

[17]  J. Delabar,et al.  The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice. , 2003, Biochemical and biophysical research communications.

[18]  J. Delabar,et al.  Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21 , 1993, European journal of human genetics : EJHG.

[19]  L. Yager,et al.  Temperature-shift analysis of conidial development in Aspergillus nidulans. , 1982, Developmental biology.

[20]  K. Osoegawa,et al.  Mapping of a novel human carbonyl reductase, CBR3, and ribosomal pseudogenes to human chromosome 21q22.2. , 1998, Genomics.

[21]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[22]  A. Aurias,et al.  Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Hattori,et al.  The DNA sequence of human chromosome 21 , 2000, Nature.

[24]  M. Bobinski,et al.  Hypothalamic abnormalities in Down syndrome. , 1991, Progress in clinical and biological research.

[25]  N. Cairns,et al.  Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease , 1997, Neuroscience Letters.

[26]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. , 1995, DNA research : an international journal for rapid publication of reports on genes and genomes.

[27]  Jérôme Lejeune,et al.  Etude des chromosomes somatiques de neuf enfants mongoliens. , 1959 .

[28]  M. Katsuki,et al.  Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome. , 1999, Human molecular genetics.

[29]  Mathura S Venkatarajan,et al.  New quantitative descriptors of amino acids based on multidimensional scaling of a large number of physical–chemical properties , 2001 .

[30]  M Heisenberg,et al.  minibrain: A new protein kinase family involved in postembryonic neurogenesis in Drosophila , 1995, Neuron.

[31]  Stephen T. Crews,et al.  The Drosophila single-minded gene encodes a nuclear protein with sequence similarity to the per gene product , 1988, Cell.

[32]  X. Estivill,et al.  A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. , 1996, Human molecular genetics.

[33]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.