RESUMO
Rab35 (Ras-associated binding protein) is a small GTPase that regulates endosomal membrane trafficking and functions in cell polarity, cytokinesis, and growth factor signaling. Altered Rab35 function contributes to progression of glioblastoma, defects in primary cilia formation, and altered cytokinesis. Here, we report a pediatric patient with global developmental delay, hydrocephalus, a Dandy-Walker malformation, axial hypotonia with peripheral hypertonia, visual problems, and conductive hearing impairment. Exome sequencing identified a homozygous missense variant in the GTPase fold of RAB35 (c.80G>A; p.R27H) as the most likely candidate. Functional analysis of the R27H-Rab35 variant protein revealed enhanced interaction with its guanine-nucleotide exchange factor, DENND1A and decreased interaction with a known effector, MICAL1, indicating that the protein is in an inactive conformation. Cellular expression of the variant drives the activation of Arf6, a small GTPase under negative regulatory control of Rab35. Importantly, variant expression leads to delayed cytokinesis and altered length, number, and Arl13b composition of primary cilia, known factors in neurodevelopmental disease. Our findings provide evidence of altered Rab35 function as a causative factor of a neurodevelopmental disorder.
Assuntos
Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento , Proteínas rab de Ligação ao GTP , Feminino , Humanos , Masculino , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Linhagem Celular , Cílios/metabolismo , Cílios/genética , Cílios/patologia , Citocinese/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mutação com Perda de Função , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Modelos Moleculares , Estrutura Terciária de ProteínaRESUMO
OBJECTIVE: We investigated the prevalence, onset, characteristics, and long-term course of epilepsy disease in children who underwent surgical intervention for diagnosed brain tumors. METHODS: We reviewed the medical records of children with diagnosed brain tumors who underwent surgery during 2004-2014 at the Hadassah Medical Center. All patients with epilepsy were invited to a clinical visit that included a neurologic examination. The primary outcome measures were neurologic status according to the Glasgow outcome score (GOS) and postoperative seizure outcome according to the Engel system. We compared clinical characteristics according to the timing of epilepsy onset. RESULTS: The mean follow-up was 49 months. Of 128 patients included in the study, 44 (34%) had seizures; 23 (18%) developed epilepsy after surgery. Of the 30 patients with epilepsy who survived, 21 (70%) are in Engel class I and 13% Engel are in class II. Forty-five percent of the children are classified as GOS 5. Children who developed epilepsy after surgery were more likely to be in GOS 1-2 than were those who had seizures before surgery (P = 0.0173). Children with seizures were more likely to have cortical tumors and less likely to have tumors of the posterior fossa (P < 0.001). Children who underwent gross total resection were less likely to have epilepsy (P < 0.001). CONCLUSIONS: We show a high incidence of epilepsy in the late course of pediatric brain tumor disease. In the long term, seizure outcome was excellent. However, postsurgical onset of epilepsy was associated with a less favorable neurologic outcome.