Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome

Nadja Ehmke; Almuth Caliebe; Rainer Koenig; Sarina G Kant; Zornitza Stark; Valérie Cormier-Daire; Dagmar Wieczorek; Gabriele Gillessen-Kaesbach; Kirstin Hoff; Amit Kawalia; Holger Thiele; Janine Altmüller; Björn Fischer-Zirnsak; Alexej Knaus; Na Zhu; Verena Heinrich; Celine Huber; Izabela Harabula; Malte Spielmann; Denise Horn; Uwe Kornak; Jochen Hecht; Peter M Krawitz; Peter Nürnberg; Reiner Siebert; Hermann Manzke; Stefan Mundlos

doi:10.1016/j.ajhg.2014.11.004

Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome

Am J Hum Genet. 2014 Dec 4;95(6):763-70. doi: 10.1016/j.ajhg.2014.11.004.

Authors

Nadja Ehmke¹, Almuth Caliebe², Rainer Koenig³, Sarina G Kant⁴, Zornitza Stark⁵, Valérie Cormier-Daire⁶, Dagmar Wieczorek⁷, Gabriele Gillessen-Kaesbach⁸, Kirstin Hoff⁹, Amit Kawalia¹⁰, Holger Thiele¹⁰, Janine Altmüller¹¹, Björn Fischer-Zirnsak¹², Alexej Knaus¹², Na Zhu¹³, Verena Heinrich¹³, Celine Huber⁶, Izabela Harabula¹⁴, Malte Spielmann¹², Denise Horn¹³, Uwe Kornak¹⁵, Jochen Hecht¹⁵, Peter M Krawitz¹⁵, Peter Nürnberg¹⁶, Reiner Siebert², Hermann Manzke¹⁷, Stefan Mundlos¹⁸

Affiliations

¹ 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.
² Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
³ Institute of Human Genetics, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
⁴ Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
⁵ Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
⁶ Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne PARIS Cité, Imagine Institute, Hôpital Necker Enfants Males, 75015 Paris, France.
⁷ Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
⁸ Institut für Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
⁹ 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.
¹⁰ Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
¹¹ Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
¹² Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
¹³ Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
¹⁴ Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
¹⁵ 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.
¹⁶ 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.
¹⁷ Private, 24226 Heikendorf, Germany.
¹⁸ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Amino Acid Sequence
Child, Preschool
Exome / genetics
Female
Hand Deformities, Congenital / enzymology
Hand Deformities, Congenital / genetics*
Haplotypes
Heterozygote
Homozygote
Humans
Infant
Male
Middle Aged
Models, Molecular
Molecular Sequence Data
Mutation
Oxidoreductases / genetics*
Oxidoreductases / metabolism
Pedigree
Pierre Robin Syndrome / enzymology
Pierre Robin Syndrome / genetics*
Sequence Alignment
Sequence Analysis, DNA
Young Adult

Substances

Oxidoreductases

Supplementary concepts

Catel Manzke syndrome