RESUMEN
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 ß-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.
Asunto(s)
Encéfalo/metabolismo , Cutis Laxo/congénito , Hamartoma/genética , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos/genética , Mutación , Anomalías Cutáneas/genética , Piel/metabolismo , Tubulina (Proteína)/genética , Adolescente , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Niño , Cutis Laxo/genética , Cutis Laxo/metabolismo , Cutis Laxo/patología , Femenino , Dosificación de Gen , Regulación del Desarrollo de la Expresión Génica , Genes Recesivos , Hamartoma/metabolismo , Hamartoma/patología , Haploinsuficiencia , Humanos , Lactante , Patrón de Herencia , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/metabolismo , Microtúbulos/patología , Pliegue de Proteína , Multimerización de Proteína , Piel/crecimiento & desarrollo , Piel/patología , Anomalías Cutáneas/metabolismo , Anomalías Cutáneas/patología , Tubulina (Proteína)/metabolismo , Adulto Joven , Pez CebraRESUMEN
Congenital symmetrical circumferential skin creases are a rare feature, often described as the "Michelin Tire Baby" syndrome and in general having a good prognosis. In some patients however, the circumferential skin creases are associated with other congenital malformations. We describe 2 unrelated patients presenting with multiple circumferential skin creases, growth retardation, developmental delay, a typical facial appearance and cleft palate. In literature, 6 patients with an almost identical clinical phenotype have been described. This well recognizable syndrome should be distinguished from the "Michelin Tire Baby" syndrome and we therefore propose the term "circumferential skin creases Kunze type".