A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse

AbstractPathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.

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Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21249707 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9707

Author(s):

Ivano Di Meo ◽

Chiara Cavestro ◽

Silvia Pedretti ◽

Tingting Fu ◽

Simona Ligorio ◽

...

Keyword(s):

Mouse Model ◽

Iron Homeostasis ◽

Axonal Neuropathy ◽

Autosomal Recessive Disorder ◽

Premature Death ◽

Iron Accumulation ◽

Motor Deficits ◽

Brain Iron ◽

Knock Out ◽

Neurological Phenotype

COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present.

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Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽

10.1007/s10048-021-00667-0 ◽

2021 ◽

Author(s):

Chiara Cavestro ◽

Celeste Panteghini ◽

Chiara Reale ◽

Alessia Nasca ◽

Silvia Fenu ◽

...

Keyword(s):

Early Onset ◽

Cerebellar Atrophy ◽

Iron Accumulation ◽

Brain Iron ◽

Causative Gene ◽

Coding Regions ◽

Aberrant Transcript ◽

Pathogenic Variants ◽

Intronic Mutation ◽

Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

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