CRISPR/Cas9-based therapies hold an important promise for the treatment of genetic diseases. Among these, Hutchinson-Gilford progeria syndrome (HGPS) – caused by a point mutation in the
LMNA
gene – stands out as a potential candidate. Here, we explore the efficacy of a CRISPR/Cas9-based approach that reverts several alterations in HGPS cells and mice by introducing frameshift mutations in the
LMNA
gene.
Giant tortoises are amongst the longest-lived vertebrate animals and as
such provide an excellent model to study traits like longevity and age-related
diseases. However, genomic and molecular evolutionary information on giant
tortoises is scarce. Here, we describe a global analysis of the genomes of
Lonesome George, the iconic last member of
Chelonoidis
abingdonii
, and the Aldabra giant tortoise (
Aldabrachelys
gigantea
). The comparison of these genomes to those of related
species, using both unsupervised and supervised analyses, led us to detect
lineage-specific variants affecting DNA repair genes, inflammatory mediators and
genes related to cancer development. Our study also hints at specific
evolutionary strategies linked to increased lifespan and expands our
understanding of the genomic determinants of ageing. These new genome sequences
also provide important resources to help the efforts for restoration of giant
tortoise populations.
Patient now 19 years old has intellectual disability, developmental delay, absent speech, seizures, hypotonia, severe motor disability (non-ambulatory), short stature, relative macrocephaly. Patient uses gastric tube for feeding and has gastroesophageal reflux. Facial dysmorphisms include short palpebral fissures, large incisors, full eyebrows. Fingers are short and trident-shaped.Brain MRI revealed progressive cerebral and cerebellar volume loss, hypodensity in the left basal ganglia, unchanged and consistent with a lacune infarct (remote). There is a less conspicuous area of hypodensity on the contralateral side. There are hypodense white matter changes along the periventricular white matter and bilateral centrum semiovale.
AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.