Genetics, Gene Therapy & Genetic Disease

CHCHD10 Q108P disrupts mitochondrial import resulting in reduced protein half‐life time.

CHCHD10 reduction results in smaller spare respiratory capacity.

Mia40 imports CHCHD10 into mitochondria through disulfide‐bond formation in the CHCH domain.

Overexpression of Mia40 restores mitochondrial targeting of CHCHD10 Q108P.

In a cohort of 23 infertile women from North Africa with oocyte meiotic deficiency (OMD), a truncating mutation in the gene PATL2, encoding an RNA‐binding protein, was identified in 26% of patients.

Patl2 knockout female mice presented severe subfertility, confirming the human diagnostic. Patl2 knockout mouse oocytes could progress to the MII stage, however with numerous morphological defects hampering normal fertilisation and development.

Patl2 is not detectable in primordial follicle oocytes, but is strongly expressed during oocyte growth and remains detectable at least until the MII stage.

Patl2 has a unique expression pattern from primordial follicle‐stage to MII‐stage oocytes and did not colocalise with Cpeb1, Msy2 or Ddx6 known to stabilise mRNA during oocyte growth.

Patl2 deficiency leads to a down or up‐regulation of a subset of mRNAs encoding proteins which are crucial for oocyte meiotic progression and early embryonic development, with no effect on the GV‐MII transition.

P110 suppresses mitochondrial dysfunction in patient‐derived fibroblasts, SOD1 G93A NSC‐34 cells and in ALS model mice.

P110 reduces muscular mitochondrial pathology and oxidative stress in ALS model mice.

P110 enhances motor activity in ALS model mice.

Drugs that improve mitochondrial function, such as P110, may provide benefits for patients with motor neuron diseases that show mitochondrial defects.

siRNA targeting the mutant allele leads to functional restoration of the impaired endocytosis in mutant human fibroblasts.

Early intra‐muscular administration of AAV1 expressing allele‐specific shRNA prevents the disease in the mouse model.

Late treatment in the disease's time course partially improve the phenotype due to a weaker transduction capacity of the muscle.

Allele‐specific silencing is a promising therapeutic strategy for AD‐CNM.