title: Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.
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.
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory for Genetics of Cognition, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Mala
authors.initials: M
authors.lastname: Isrie
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Breuss
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Andi Harley
authors.initials: AH
authors.lastname: Hansen
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cristofoli
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Morandell
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Zachari A
authors.initials: ZA
authors.lastname: Kupchinsky
authors.affiliation: Department of Electrical Engineering, STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, 3001 Heverlee, Belgium.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sifrim
authors.affiliation: Department of Paediatrics, Ourense Hospital Complex, 32005 Ourense, Spain.
authors.forename: Celia Maria
authors.initials: CM
authors.lastname: Rodriguez-Rodriguez
authors.affiliation: Department of Paediatrics, Ourense Hospital Complex, 32005 Ourense, Spain.
authors.forename: Elena Porta
authors.initials: EP
authors.lastname: Dapena
authors.affiliation: Medical Genetics Services, University of Alberta and Stollery Children's Hospital, Edmonton, AB T6G 2C8, Canada.
authors.forename: Kurston
authors.initials: K
authors.lastname: Doonanco
authors.affiliation: Medical Genetics Services, University of Alberta and Stollery Children's Hospital, Edmonton, AB T6G 2C8, Canada.
authors.forename: Norma
authors.initials: N
authors.lastname: Leonard
authors.affiliation: Department of Pediatrics B, Children's Hospital of Tunis, 1007 Tunis, Tunisia.
authors.forename: Faten
authors.initials: F
authors.lastname: Tinsa
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Moortgat
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, 34098 Istanbul, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Ulucan
authors.affiliation: Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, 34303 Istanbul, Turkey.
authors.forename: Erkan
authors.initials: E
authors.lastname: Koparir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Medical Genetics, the Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Valeria
authors.initials: V
authors.lastname: Marton
authors.affiliation: 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.
authors.forename: Joris Robert
authors.initials: JR
authors.lastname: Vermeesch
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowan
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: David Anthony
authors.initials: DA
authors.lastname: Keays
authors.affiliation: 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: hilde.vanesch@med.kuleuven.be.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002648:Child; D003483:Cutis Laxa / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive; D006222:Hamartoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D012867:Skin / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D015027:Zebrafish
chemical_list: C588005:MAPRE2 protein, human; D008869:Microtubule-Associated Proteins; C578986:TUBB1 protein, human; D014404:Tubulin
keywords: MAPRE2; Michelin tire baby; TUBB; circumferential skin creases; exome sequencing; tubulinopathy