Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome PMID: 25480037

RQC and Longevity Regulation

2026-09-03

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.

Nadja Ehmke ¹ , Almuth Caliebe ² , Rainer Koenig ³ , Sarina G Kant ⁴ , Zornitza Stark ⁵ , Valérie Cormier-Daire ⁶ , Dagmar Wieczorek ⁷ , Gabriele Gillessen-Kaesbach ⁸ , Kirstin Hoff ⁹ , Amit Kawalia ¹⁰ , Holger Thiele ¹⁰ , Janine Altmüller ¹¹ , Björn Fischer-Zirnsak ¹² , Alexej Knaus ¹² , Na Zhu ¹³ , Verena Heinrich ¹³ , Celine Huber ⁶ , Izabela Harabula ¹⁴ , Malte Spielmann ¹² , Denise Horn ¹³ , Uwe Kornak ¹⁵ , Jochen Hecht ¹⁵ , Peter M Krawitz ¹⁵ , Peter Nürnberg ¹⁶ , Reiner Siebert ² , Hermann Manzke ¹⁷ , Stefan Mundlos ¹⁸

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: [email protected].
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: [email protected].

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.