Posts By: Nicola Brunetti-Pierri

Whole Exome Sequencing in Inborn errors of metabolism

Posted by & filed under Exome sequencing, Part 06: DIAGNOSTIC APPROACHES.

Therapies are becoming increasingly avaible for inborn errors of metabolism making diagnosis of these disorders particularly improtant. The New England Journal of Medicine recently published a study on whole-exome sequencing in 41 patients resulting in a diagnosis in 28 of them (68%) and a targeted intervention in 18 of them (44%). The relatively high diagnostic yield found in this study may stem […]

Autism-like behaviours in transgenic monkeys overexpressing MeCP2

Posted by & filed under Part 28: NEUROGENETICS.

MECP2 gene is mutated in Rett syndrome and MECP2 duplication is responsible for a severe developmental disorder with autistic phenotypes. A recent work published in Nature reports the generation of MECP2 transgenic monkeys. The transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. […]

Beta-mannosidase gene mutations in autosomal dominant nystagmus

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

A recent study in Genetics in Medicine aiming at the identification by whole-exome sequencing of genes involved in infantile nystagmus found heterozygous missense mutations in the MANBA gene, which the encodes lysosomal beta-mannosidase. The mutations resulted in decrease of ?-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. MANBA is expressed in the pretectal nucleus of the developing midbrain, […]

AAV gene therapy for Batten disease

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

In this work, Beverly Davidson’s group investigated delivery of the gene encoding the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1) enzyme to the ependymal cells in a dog model of a Batten disease.  They show that this strategy delayed disease onset, extended life span, and protected dogs from early cognitive decline, suggesting that this approach could improve the […]

Losartan therapy for dystrophic epidermolysis bullosa

Posted by & filed under Part 27: SKIN.

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. No effective therapies are available. Based on the findings that TGF-beta activity is elevated in injured RDEB skin, Nystrom and colleagues targeted TGF-beta activity with losartan in RDEB mice. Long-term treatment with […]

AAV2-related insertional mutagenesis in human hepatocellular carcinomas: implications for gene therapy

Posted by & filed under Part 02: PERSPECTIVES.

Adeno-associated viral (AAV) vectors have been increasingly used for gene therapy in preclinical and clinical studies. In liver-directed approaches the AAV vectors have emereged as the most promising gene transfer vector in terms of safety and efficacy. A few studies have found increased incidence of hepatocellular carcinomas (HCCs) in mice injected with AAV vectors as […]

Recurrent mutations in NF1 and RASopathy genes melanomas

Posted by & filed under Part 04: CANCER.

A whole-exome sequencing (WES) study on 213 melanomas found that NF1, encoding a negative regulator of RAS mutated in Neurofibromatosis type 1, is the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern […]

Engineering the gut microbiota to treat hyperammonemia

Posted by & filed under Part 08: AMINO ACIDS.

Gut microbiota can be altered to ameliorate or prevent disease states. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. In their JCI paper, Shen and colleagues engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting […]

Role of GABA Receptors for synaptic plasticity and memory in Down syndrome

Posted by & filed under Part 05: CHROMOSOMES.

Altered GABAergic transmission through Cl–-permeable GABAA receptors (GABAARs) is known to contribute to learning and memory deficits in Down syndrome mouse models. In this study, GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl– currents (ECl) was shifted toward more positive potentials in the hippocampi of adult Down syndrome mice. Hippocampal expression of […]

Brain somatic mutations in MTOR cause focal cortical dysplasia and epilepsy

Posted by & filed under Part 28: NEUROGENETICS.

Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. Using deep whole-exome sequencing in paired brain-blood DNA from subjects with FCDII, Lim et al. uncovered brain somatic mutations in mechanistic target of rapamycin (MTOR). The identified mutations induced the hyperactivation of […]