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1 from the 2000 ASHG Annual Meeting Mutations in the EGF-CFC

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1 from the 2000 ASHG Annual Meeting Mutations in the EGF-CFC Program Nr: 1 from the 2000 ASHG Annual Meeting Mutations in the EGF-CFC gene, CRYPTIC, cause human Left-Right axis abnormalities and Transposition of the Great Arteries. R.N. Bamford1, J. dela Cruz1, E. Roessler1, U. Saplakoglu2, R. Burdine3, E. Goldmuntz4, M. Shen2, A. Schier3, B. Casey5, M. Muenke1. 1) Medical Genetics Branch, NHGRI/NIH, Bethesda, MD; 2) Robert Wood Johnson Medical School, Piscataway, NJ; 3) Skirball Institute, NYU, NY; 4) The Children's Hospital of Philadelphia, PA; 5) Baylor College of Medicine, Houston, TX. Studies in zebrafish and mice demonstrate that the EGF-CFC proteins (oep/Cripto/Cryptic) play critical roles in the establishment of left-right (L-R) and anterior-posterior (A-P) axis formation as essential co-factors for cyclops/squint/Nodal proteins. Here we investigated the potential genetic role of CRYPTIC in human laterality disorders such as, situs inversus, situs ambiguus and isomerism of normally asymmetric organs. Although Transposition of the Great Arteries (TGA) is often seen in patients manifesting other situs complications, isolated TGA is felt to represent a unique disorder. Therefore, we also screened TGA patients for CRYPTIC mutations to determine if this disorder can be placed within the laterality spectrum. Although the CRIPTO gene had been characterized in humans, the CRYPTIC gene had not been analyzed. We cloned and characterized the human CRYPTIC gene, its cDNA, and performed mutational studies on genomic DNA from laterality and TGA patients. We have identified three missense and one frameshift mutation in the CRYPTIC gene of patients with laterality defects. In TGA patients, one unique splice-donor mutation has been identified, however, two mutations originally identified in laterality patients were also seen in two TGA patients. These nucleotide changes were not detectable in over 200 chromosomes from normal controls. Phenotypic rescue studies utilizing oep zebrafish mutants and cellular localization studies confirm the significance of these mutations in functional studies. In summary, our results demonstrae a role for CRYPTIC in the pathogenesis of human laterality defects and suggest that TGA can be included within the spectrum of laterality disorders. Copyright © 2000 The American Society of Human Genetics. All rights reserved. Program Nr: 2 from the 2000 ASHG Annual Meeting Genome-wide comparison of human genetic and physical maps. A. Yu1, C. Zhao1, K.W. Broman2, W. Jang3, A.J. Mungall4, I. Dunham4, J.L. Weber1. 1) Center for Medical Genetics, Marshfield Medical Research Foundation, Marshfield, WI; 2) Department of Biostatistics, Johns Hopkins University, Baltimore, MD; 3) National Center for Biotechnology Information, NLM, NIH, Bethesda, MD; 4) The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. Completion of draft and near complete human chromosomal DNA sequences permits a genome-wide analysis of the relationship between genetic and physical map distances. Using computer searches we have identified BAC sequences which encompass about 70% of the 8000 short tandem repeat polymorphisms (STRPs) on our most recent comprehensive genetic maps (Broman et al. Am. J. Hum. Genet. 63:861-869, 1998). Reasons for the 30% failure are not completely understood, but likely involve absence of the appropriate BAC sequence from the public database and the presence of interspersed repeats within the STR sequence. At the time of abstract submission (June 2000), we have obtained reliable physical distances in nucleotides between STRPs for three chromosomes: 6, 21 and 22. Physical distances for the remaining chromosomes are likely to become available in the near future. Comparison of the genetic and physical maps helps identify errors in the maps, regions of high and low recombination, and even putative inversion polymorphisms. For chromosomes 6, 21, and 22, marker orders agreed well between the genetic and physical maps. Only four STRPs appeared to be positioned with large error. Overall recombination rates (sex-average) for the three chromosomes ranged from 1.1 to 1.9 and averaged 1.24 cM/mb. For many chromosomal regions, female and male recombination rates changed in parallel, but for other regions there were large gender differences. Regions with particularly low recombination, near 0 cM/mb and spanning 6 - 12 mb, were found on all three chromosomes. Genes within these recombination deserts may be particularly amenable to mapping by association. Regions with particularly high average recombination, up to about 6 cM/mb were also identified. It is unknown if these recombination jungles have uniformly high levels of recombination or are in turn comprised of shorter regions of high and low recombination. Copyright © 2000 The American Society of Human Genetics. All rights reserved. Program Nr: 3 from the 2000 ASHG Annual Meeting Tandem mass spectrometry newborn screening for medium-chain acyl-CoA dehydrogenase deficiency in North Carolina. S.E. McCandless1, J. Muenzer1, S.H. Chaing2, S.D. Weavil2, E.G. Moore2, D.M. Frazier1. 1) Department of Pediatrics, Univ North Carolina, Chapel Hill, NC; 2) Division of Public Health, Raleigh, NC. In 8/97 the state of North Carolina (NC) expanded its newborn screening program by addition of tandem mass spectrometry (TMS) to detect a variety of metabolic disorders, including medium-chain acyl-CoA dehydrogenase deficiency (MCADD). From 8/97 to 4/99 the tests were performed by Neo Gen Screening, Inc. (Pittsburgh, PA). Since 4/99 screening has been performed by the NC State Newborn Screening Laboratory. As of 6/00 327,031 infants from NC (71% Caucasian) had been screened. Abnormal follow-up plasma acylcarnitine profile and/or urine organic acid analysis, or documentation of homozygosity for the A985G mutation confirmed suspected MCADD. To date, 24 asymptomatic infants with MCADD have been identified by TMS screening. Of these, 23 were Caucasian, giving an incidence of MCADD of 1:10,095 in that population. All of the Caucasian children tested had at least one copy of the common A985G mutation with 70% (14/20) homozygous. The one affected African-American infant had no copies of the common mutation. Confirmatory testing for suspected MCADD was striking. A985G homozygotes had a mean C8- acylcarnitine of 3.46 mM (nl<0.25) and mean C8/C10 ratio of 14.2 (nl=0.9), while MCADD infants with only one copy of A985G had a mean C8 of 1.10 mM and a mean C8/C10 ratio of 3.2. All infants were treated with carnitine and were maintained on breast milk or regular infant formula with no fat restriction in the first year of life. Parents were instructed to avoid prolonged fasting and to use glucometers to monitor blood glucose when they were concerned about the child's oral intake or clinical status. During 36.5 patient years of follow-up, 2 patients have been admitted a total of 4 times for IV glucose due to inadequate oral intake of fluids. There have been no deaths, no significant hypoglycemia, and no seizures in MCADD children identified by TMS screening. All children are developmentally normal so far. Our initial experience demonstrates that newborn screening by TMS, with careful follow-up, can prevent most, if not all, deaths and serious sequelae of MCADD in the first few years of life. Copyright © 2000 The American Society of Human Genetics. All rights reserved. Program Nr: 4 from the 2000 ASHG Annual Meeting Htra2-beta1 restores full-length SMN2 expression by activating an exonic splicing enhancer; An exciting target for therapy in spinal muscular atrophy. B. Wirth1, Y. Hofmann1, C.L. Lorson2, S. Stamm3, E.J. Androphy2. 1) Dept Molecular Genetics, Inst Human Genetics, Bonn, Germany; 2) Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA; 3) Max-Planck-Institute of Neurobiology, Martinsried, Germany. Spinal muscular atrophy (SMA), the second most frequent autosomal recessive disorder in human is a motor neuron disease that results from loss of functional survival motor neuron (SMN1) alleles. A nearly identical copy of the gene, SMN2, fails to provide protection from SMA due to a single translationally silent nucleotide difference in exon 7. This likely disrupts an exonic splicing enhancer (ESE) and causes exon 7 skipping leading to abundant production of a shorter isoform, SMN2delta7. The truncated transcript encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the loss of SMN1. This report describes the identification of an in vivo regulator of SMN mRNA processing. Htra2-beta1, an SR-like, non-essential splicing factor and ortholog of Drosophila melanogaster transformer-2, promoted the inclusion of SMN exon 7 and stimulated full-length SMN2 expression to almost 90%. Htra2-beta1 specifically functioned through and bound an AG-rich ESE in SMN exon 7. This effect is not species specific as expression of Htra2-beta1 in human or mouse cells carrying an SMN2 minigene dramatically increases production of full-length SMN2. This demonstrates that SMN2 mRNA processing can be modulated in vivo. Since all SMA patients retain at least one SMN2 copy, the prevention of exon 7 skipping by upregulating the full-length product of SMN2 by Htra2-beta1 represents an exciting target for SMA therapy. Copyright © 2000 The American Society of Human Genetics. All rights reserved. Program Nr: 5 from the 2000 ASHG Annual Meeting Variability and Pathogenesis of DiGeorge Syndrome in Mice. E.A. Lindsay, F. Vitelli, T. Pramparo, T. Huynh, A. Baldini. Pediatrics - Cardiology, Baylor Col Medicine, Houston, TX. DiGeorge syndrome (DGS) is an archetypal cranial/cardiac neurocristopathy that includes aortic arch and outflow tract defects, and aplasia/hypoplasia of the thymus and parathyroids. DGS is caused by a ~3 Mb heterozygous deletion of 22q11.2 (del22q11). We have generated a mouse model of del22q11 that carries a chromosomal deletion (Df1) that eliminates most of the murine homologs of genes deleted in DGS. In a C57Bl6x129SvEv, mixed genetic background, Df1 causes CHD but not thymic or parathyroid defects.
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