Posts By: Nicola Brunetti-Pierri

Mechanisms of ammonia neurotoxicity unraveled

Posted by & filed under Part 08: AMINO ACIDS.

Excess of ammonia causes neurological dysfunction ranging from cognitive impairment to tremor, ataxia, seizures, coma and death. The brain is especially vulnerable to ammonia as it readily crosses the blood-brain barrier in its gaseous form, NH3, and rapidly saturates its principal removal pathway located in astrocytes. Rangroo Thrane and colleagues used a combination of two-photon imaging […]

SHANK3 overexpression causes manic-like behaviour

Posted by & filed under Part 28: NEUROGENETICS.

Large duplications (and deletions) of the region spanning SHANK3 cause a spectrum of neuropsychiatric disorders. Therefore, SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. This study reports that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit […]

Synaptic deficits in neurons from 22q13 deletion syndrome patients is restored by SHANK3 and IGF1

Posted by & filed under Part 05: CHROMOSOMES.

Microdeletion of 22q13 region encompassing SHANK3 gene and rare heterozygous mutations in SHANK3 have been associated with neurodevelopmental disorder Phelan–McDermid syndrome (PMDS), autism spectrum disorders (ASDs), non-syndromic intellectual disability, and schizophrenia. However, the cellular and molecular phenotypes resulting from SHANK3 haploinsufficiency in human neurons are unknown. In this study, induced pluripotent stem (iPS) cells were generated from individuals with PMDS […]

CPEB1 depletion ameliorates fragile X syndrome

Posted by & filed under Part 05: CHROMOSOMES.

Fragile X syndrome (FXS) is caused by transcriptional silencing of FMR1 encoding the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element–binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, […]

Trisomy 21 correction by XIST-mediated silencing

Posted by & filed under Part 05: CHROMOSOMES.

A paper recently published in Nature reports silencing of one chromosome 21 in Down syndrome cells.  Using genome editing with zinc finger nucleases, the authors inserted an inducible XIST (the X-inactivation gene) on chromosome 21 in Down syndrome pluripotent stem cells. The XIST non-coding RNA coated chromosome 21 and triggered stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation […]

RNA interference-based therapy for transthyretin amyloidosis

Posted by & filed under Part 22: CONNECTIVE TISSUE.

Transthyretin amyloidosis is caused by deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and heart. A paper recently published in the New England Journal of Medicine reports the safety and efficacy of a potent antitransthyretin small interfering RNA (RNAi) encapsulated in lipid nanoparticles and injected in patients with transthyretin amyloidosis. The RNAi resulted in sustained reduction of […]

Hepatic disease in fatty acid oxidation defects

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

A recently published study reports the range of phenotypes of a large number (187) of French patients with fatty acid beta-oxidation defects (FAODs). The study highlights that the liver is the main organ involved at diagnosis regardless of age at diagnosis, classical phenotype (i.e. cardiac, hepatic, or muscular), or enzyme deficiency. Hepatic symptoms were present in 89% of patients […]

Cholesterol metabolism is altered in Rett syndrome

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Monica Justice and colleagues identified a mutation in Sqle encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, that suppresses the phenotype of Mecp2-null mice, a model of Rett syndrome. They also showed that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Importantly, statin drugs improve systemic perturbations of lipid metabolism, […]

Gene therapy for Wiskott-Aldrich syndrome

Posted by & filed under Part 19: BLOOD.

Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP that is treated with hematopoietic stem/progenitor cell (HSPC) transplantation. Infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach when matched donors are unavailable. Following reduced-intensity conditioning regimen, three WAS patients were infused with autologous HSPCs genetically corrected by […]

Gene therapy prevents severe outcomes of metachromatic leukodystrophy

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

The promising results of a gene therapy clinical trial for metachromatic leukodystrophy (MLD), an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency, have bee recently published in Science. Three MLD patients in a presymptomatic stage were infused with hematopoietic stem cells genetically corrected with lentiviral vectors and showed extensive and stable ARSA gene replacement, which led […]