title: Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.
abstract: Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: nadja.ehmke@charite.de.
authors.forename: Nadja
authors.initials: N
authors.lastname: Ehmke
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.affiliation: Institute of Human Genetics, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Koenig
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.affiliation: Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne PARIS Cité, Imagine Institute, Hôpital Necker Enfants Males, 75015 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Congenital Heart Disease and Pediatric Cardiology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Hoff
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kawalia
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer-Zirnsak
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Alexej
authors.initials: A
authors.lastname: Knaus
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Heinrich
authors.affiliation: Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne PARIS Cité, Imagine Institute, Hôpital Necker Enfants Males, 75015 Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Huber
authors.affiliation: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Izabela
authors.initials: I
authors.lastname: Harabula
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Private, 24226 Heikendorf, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Manzke
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. Electronic address: stefan.mundlos@charite.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D006228:Hand Deformities, Congenital / Q000201:enzymology / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010855:Pierre Robin Syndrome / Q000201:enzymology / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D010088:Oxidoreductases