Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities

作者：Brereton Emily; Fassi Emily; Araujo Gabriel C; Dodd Jonathan; Telegrafi Aida; Pathak Sheel J; Shinawi Marwan^*

来源：Molecular Genetics & Genomic Medicine, 2018, 6(2): 294-300.

DOI：10.1002/mgg3.362

• developmental delay
• domain
• dynamin 1
• epileptic encephalopathy
• intellectual disability
• synaptic vesicle

BackgroundDynamin 1 is a protein involved in the synaptic vesicle cycle, which facilitates the exocytosis of neurotransmitters necessary for normal signaling and development in the central nervous system. Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy. All previously reported DNM1 pathogenic variants causing this severe phenotype occur in the GTPase and Middle domains of the dynamin 1 protein.
MethodsWe used whole-exome sequencing to characterize the molecular basis of DD and autistic symptoms in two identical siblings.
ResultsThe twin siblings exhibit mild to moderate ID and autistic symptoms but no epileptic encephalopathy. Exome sequencing revealed a genetic variant, c.1603A>G (p.Lys535Glu), in the PH domain of dynamin 1. Previous invitro studies showed that mutations at Lys535 inhibit endocytosis and impair PH loop binding to PIP2.
ConclusionsOur data suggest a previously undescribed milder phenotype associated with a missense genetic variant in the PH domain of dynamin 1.

• 出版日期2018-3