Ricerc@Sapienza

Zimmermann-Laband syndrome (ZLS; MIM 135500) is a rare developmental disorder characterized by facial dysmorphism, gingival enlargement, nail aplasia/hypoplasia, hypertrichosis, and intellectual disability, with or without epilepsy. Recently, a whole exome sequencing based approach allowed the applicant's group to identify two disease genes (KCNH1 and ATP6V1B2). More recently, further patients with KCNH1 mutations with intellectual disability and a phenotype characterized by syndromic developmental delay, hypotonia and seizures have been reported.
The applicant proposes studies to characterize the molecular bases of ZLS. To this aim, different in vitro approaches will be used to dissect the functional mechanisms of pathogenesis. As recently reported, KCNH1 is a regulator of ciliogenesis. In order to gain insight in the deregulated mechanism caused by the ZLS causing KCNH1 missense mutations, we will examine cilium assembly and function as a potential molecular cause of dysfunction.
The functional role of KCNH1 in ciliogenesis will be assessed by evaluating the frequency of expression of cilia in wild type and mutants expressing cells. We will test also if pathogenic effect of the mutants relies on ciliary physiology. To this aim, we will characterize the subcellular localization of endogenous wild type and mutant KCNH1 on cultured skin fibroblasts obtained from subcutaneous biopsies of ZLS patients, as well as in transiently transfected cell lines.
Functional studies on disease-causing mutants could shed light on molecular network involved in the pathogenesis of this disorder characterized by multisystem involvement, providing clues on the differential effect that the causing mutations exert on ZLS related developmental processes.
Efforts aimed at disclosing molecular dysfunctions involved in pathogenesis are fundamental prerequisites that will provide molecular information with direct impact on diagnosis, prognosis, counseling, and patient management.