RESUMO
Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Membrana/genética , Microcefalia/genética , Fosfoproteínas/genética , Fatores de Transcrição/genética , Animais , Animais Geneticamente Modificados , Proteínas Relacionadas à Autofagia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas Desgrenhadas , Drosophila , Ligação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Microcefalia/patologia , Mutação , Tamanho do Órgão/genética , Via de Sinalização Wnt/genéticaRESUMO
The clinical diagnosis of ASS (Aarskog-Scott syndrome or Faciogenital Dysplasia) was made in seven individuals belonging to a large Arabic family, which was supported by molecular studies revealing a 2189delA mutation in exon 15 of the FDG1 gene. The affected individuals in this family demonstrated clinical variability particularly in their cognitive skills, raising the question whether other genetic factors might be involved in the phenotypic evolution of ASS.