Clin Genet. 2022 Aug 31. doi: 10.1111/cge.14220. Online ahead of print.
Hereditary spastic paraparesis (HSP) presenting as cerebral palsy due to ADD3 variant with mechanistic insight provided by a Drosophila γ-adducin model.
Sanchez Marco SB Buhl E, Firth R, Zhu B, Gainsborough M, Beleza-Meireles A, Moore S, Caswell R, Stals K, Ellard S, Kennedy C, Hodge JJL, Majumdar A
From the abstract:
INTRODUCTION: Cerebral palsy (CP) causes neurological disability in early childhood. Hypoxic-ischaemic injury plays a major role in its aetiology, nevertheless, genetic and epigenetic factors may contribute to the clinical presentation. Mutations in ADD3 (encoding γ-adducin) gene have been described in a monogenic form of spastic quadriplegic cerebral palsy (OMIM 601568).
METHODS: We studied a sixteen-year-old male with spastic diplegia. ... clinical genetics assessment and Whole Exome Sequencing (WES) gave the diagnosis. We generated an animal model using Drosophila to study the effects of γ-adducin loss and gain of function.
RESULTS: ... Pan-neuronal over-expression or knock-down of the Drosophila ortholog of ADD3 called hts caused a reduction of life span and impaired locomotion thereby phenocopying aspects of the human disease.
CONCLUSION: Our animal experiments present a starting point to understand the biological processes underpinning the clinical phenotype and pathogenic mechanisms, to gain insights into potential future methods for treating or preventing ADD3 related spastic quadriplegic cerebral palsy.
PMID: 36046955
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