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

TitleMutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.
Publication TypeJournal Article
Year of Publication2015
AuthorsIsrie, M, Breuss, M, Tian, G, Hansen, AHarley, Cristofoli, F, Morandell, J, Kupchinsky, ZA, Sifrim, A, Rodriguez-Rodriguez, CMaria, Dapena, EPorta, Doonanco, K, Leonard, N, Tinsa, F, Moortgat, S, Ulucan, H, Koparir, E, Karaca, E, Katsanis, N, Marton, V, Vermeesch, JRobert, Davis, EE, Cowan, NJ, Keays, DAnthony, Van Esch, H
JournalAm J Hum Genet
Date Published2015 Dec 03
KeywordsAdolescent, Animals, Brain, Child, Cutis Laxa, Female, Gene Dosage, Gene Expression Regulation, Developmental, Genes, Recessive, Hamartoma, Haploinsufficiency, Humans, Infant, Inheritance Patterns, Male, Microtubule-Associated Proteins, Microtubules, Mutation, Protein Folding, Protein Multimerization, Skin, Skin Abnormalities, Tubulin, Young Adult, Zebrafish

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID26637975
PubMed Central IDPMC4678434
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
P50DK096415 / DK / NIDDK NIH HHS / United States
R01 GM097376 / GM / NIGMS NIH HHS / United States
P50 DK096415 / DK / NIDDK NIH HHS / United States
R01GM097376 / GM / NIGMS NIH HHS / United States