Pathogenic variants in Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction.

encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate the kinesin-dependent anterograde movement of lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic variants, including four loss-of-function and two missense variants. Carriers of homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy.

Biallelic variants in encoding a subunit of the TFIIIC2 complex are associated with neurodevelopmental phenotypes in humans and zebrafish.

RNA polymerase III transcribes essential non-coding RNAs, a process regulated by transcription factors TFIIIB and TFIIIC. Although germline variants in TFIIIC subunit genes have been described in a few patients with neurodevelopmental disorders, the associated pathogenesis and clinical spectrum are not yet well defined. Herein, we describe the identification of biallelic variants in which encodes a key component of the TFIIIC subunit, in four patients from three unrelated families of different ethnicities collected through GeneMatcher.

Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.

BLOC-one-related complex (BORC) is a multiprotein complex composed of eight subunits named BORCS1-8. BORC associates with the cytosolic face of lysosomes, where it sequentially recruits the small GTPase ARL8 and kinesin-1 and -3 microtubule motors to promote anterograde transport of lysosomes toward the peripheral cytoplasm in non-neuronal cells and the distal axon in neurons. The physiological and pathological importance of BORC in humans, however, remains to be determined.

Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies.

The apoptosis pathway is a programmed cell death mechanism that is crucial for cellular and tissue homeostasis and organ development. There are three major caspase-dependent pathways of apoptosis that ultimately lead to DNA fragmentation. Cancerous cells are known to highly regulate the apoptotic pathway and its role in cancer hallmark acquisition has been discussed over the past decades.