title: Identification of four novel PCDH19 Mutations and prediction of their functional impact.
abstract: The PCDH19 gene encodes protocadherin-19, a transmembrane protein with six cadherin (EC) domains, containing adhesive interfaces likely to be involved in neuronal connection. Over a hundred mostly private mutations have been identified in girls with epilepsy, with or without intellectual disability (ID). Furthermore, transmitting hemizygous males are devoid of seizures or ID, making it difficult to establish the pathogenic nature of newly identified variants. Here, we describe an integrated approach to evaluate the pathogenicity of four novel PCDH19 mutations. Segregation analysis has been complemented with an in silico analysis of mutation effects at the protein level. Using sequence information, we compared different computational prediction methods. We used homology modeling to build structural models of two PCDH19 EC-domains, and compared wild-type and mutant models to identify differences in residue interactions or biochemical properties of the model surfaces. Our analysis suggests different molecular effects of the novel mutations in exerting their pathogenic role. Two of them interfere with or alter functional residues predicted to mediate ligand or protein binding, one alters the EC-domain folding stability; the frame-shift mutation produces a truncated protein lacking the intracellular domain. Interestingly, the girl carrying the putative loss of function mutation presents the most severe phenotype.
authors.affiliation: Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leonardi
authors.affiliation: Pediatric Neurology Unit, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sartori
authors.affiliation: Pediatric Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Vecchi
authors.affiliation: Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bettella
authors.affiliation: Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Polli
authors.affiliation: Pediatric Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Luca De
authors.initials: LD
authors.lastname: Palma
authors.affiliation: Pediatric Neurophysiology Unit, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Boniver
authors.affiliation: Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Padua, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Murgia
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D017434:Protein Structure, Tertiary; D000091363:Protocadherins; D055815:Young Adult
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins
keywords: EFMR; PCDH19; epilepsy; in silico analysis; pathogenicity