Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type

Am J Hum Genet. 2015 Dec 3;97(6):790-800. doi: 10.1016/j.ajhg.2015.10.014.

Mala Isrie ¹, Martin Breuss ², Guoling Tian ³, Andi Harley Hansen ², Francesca Cristofoli ⁴, Jasmin Morandell ², Zachari A Kupchinsky ⁵, Alejandro Sifrim ⁶, Celia Maria Rodriguez-Rodriguez ⁷, Elena Porta Dapena ⁷, Kurston Doonanco ⁸, Norma Leonard ⁸, Faten Tinsa ⁹, Stéphanie Moortgat ¹⁰, Hakan Ulucan ¹¹, Erkan Koparir ¹², Ender Karaca ¹³, Nicholas Katsanis ⁵, Valeria Marton ¹⁴, Joris Robert Vermeesch ¹⁵, Erica E Davis ⁵, Nicholas J Cowan ³, David Anthony Keays ², Hilde Van Esch ¹⁶

Affiliations

1 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory for Genetics of Cognition, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
2 Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
3 Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA.
4 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
5 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
6 Department of Electrical Engineering, STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, 3001 Heverlee, Belgium.
7 Department of Paediatrics, Ourense Hospital Complex, 32005 Ourense, Spain.
8 Medical Genetics Services, University of Alberta and Stollery Children's Hospital, Edmonton, AB T6G 2C8, Canada.
9 Department of Pediatrics B, Children's Hospital of Tunis, 1007 Tunis, Tunisia.
10 Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium.
11 Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, 34098 Istanbul, Turkey.
12 Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, 34303 Istanbul, Turkey.
13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
14 Department of Medical Genetics, the Arctic University of Norway, 9037 Tromsø, Norway.
15 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory for Cytogenetics and Genome Research, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
16 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory for Genetics of Cognition, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium. Electronic address: [email protected].

PMID: 26637975 DOI: 10.1016/j.ajhg.2015.10.014

Abstract

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

Keywords

MAPRE2; Michelin tire baby; TUBB; circumferential skin creases; exome sequencing; tubulinopathy.

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