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

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. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

Mala Isrie, Martin Breuss, Guoling Tian, Andi Harley Hansen, Francesca Cristofoli, Jasmin Morandell, Zachari A Kupchinsky, Alejandro Sifrim, Celia Maria Rodriguez-Rodriguez, Elena Porta Dapena, Kurston Doonanco, Norma Leonard, Faten Tinsa, Stéphanie Moortgat, Hakan Ulucan, Erkan Koparir, Ender Karaca, Nicholas Katsanis, Valeria Marton, Joris Robert Vermeesch, Erica E Davis, Nicholas J Cowan, David Anthony Keays, Hilde Van Esch. Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type. American journal of human genetics. 2015 Dec 03;97(6):790-800

Mesh Tags

Substances

PMID: 26637975

search → result