Phenotypic and genetic characterization of the Atp7a mottled mouse: A new murine model of Menkes disease

Mototani, Yasumasa; Miyoshi, Isao; Okamura, Tadashi; Moriya, Takuya; Meng, Yan; Pei, Xiang Yuan; Kameo, Satomi; Kasai, Noriyuki

doi:10.1016/j.ygeno.2005.09.011

Cited by 15 publications

(13 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ICR mouse strain tends to show less extreme gene disruption effects than those of other mouse strains [24], [25]. We therefore intercrossed UTF1 heterozygous mutant mice, which have a C57BL/6J background, with wild-type ICR mice and backcrossed the F1 progeny with ICR mice.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

et al. 2013

View full text Add to dashboard Cite

Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. UTF1 is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the UTF1 gene during mouse development. We found that homozygous UTF1 mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of UTF1 expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of UTF1 expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the UTF1 gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the UTF1 genes.

show abstract

Section: Resultsmentioning

confidence: 99%

In Vivo Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

et al. 2013

View full text Add to dashboard Cite

show abstract

“…146,152 To begin to assess the safety and efficacy of postnatal gene-based therapies that could be relevant to human newborns with Menkes disease, we designed a brain-directed treatment approach for mottled brindled C57BL/6J mice. A combination of gene therapy with AAV5 harboring a truncated (owing to AAV vector packaging limits) but functional version of ATP7A, plus copper chloride, both delivered by intra cerebroventricular injection, enhanced the survival of mottled brindled males in comparison with no treatment.…”

Section: Models Of Atp7a-related Diseasementioning

confidence: 99%

ATP7A-related copper transport diseases—emerging concepts and future trends

2011

View full text Add to dashboard Cite

This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder—isolated distal motor neuropathy—has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot–Marie–Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.

show abstract

“…Most of the mottled mutations arise spontaneously and Atp7a mutations have been defined in 12 mottled mutants until now. [44][45][46] The mottled brindled (Mo br ) and mottled macular (Mo ml ) are the closest models to the classical form of MD. They both present with severe neurological impairment and hemizygous males die in the postnatal period (1-3 weeks).…”

Section: Animal Modelsmentioning

confidence: 99%