Hebbar, M. | Search bioRxiv

bioRxiv2022

Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome

THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 facilitates the formation of the Transcription Export complex (TREX) tetramer, composed of four THO monomers. The TREX tetramer supports mammalian mRNA processing that is distinct from yeast TREX dimer functions. Human and mouse TIDS model systems allow novel THOC6-dependent TREX tetramer functions to be investigated. Biallelic loss-of-function (LOF) THOC6 variants do not influence the expression and localization of TREX members in human cells, but our data suggests reduced binding affinity of ALYREF. Impairment of TREX nuclear export functions were not detected in cells with biallelic THOC6 LOF. Instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing novel insights into THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions that may inform TIDS neuropathology.

molecular biology↗

bioRxiv2016

Homozygous c.259G>A variant in ISCA1 is associated with a new multiple mitochondrial dysfunctions syndrome

The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2 are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS) among other human diseases. MMDS are clinically characterized by neurodevelopmental delay, neurological deterioration, lactic acidosis, extensive white matter abnormalities and early death. We report on two unrelated families, with two affected children each with neurodevelopmental delay, regression of developmental milestones, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Exome sequencing of two affected individuals, one from each family, revealed a homozygous c.259G>A variant in ISCA1 and Mendelian segregation was confirmed in both families. ISCA1 is a specialized factor known to mediate maturation of distinct Fe-S cluster (ISC) proteins. In silico functional analyses and structural modeling of the protein predict the identified ISCA1 variant to be detrimental to protein stability and function. Notably the phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all 4 types of MMDS. The ISCA1 variant lies in the only shared region of homozygosity between the two families suggesting the possibility of a founder effect. To the best of our knowledge this is the first instance where ISCA1 deficiency has been shown to be associated with a human disease, a new type of multiple mitochondrial dysfunctions syndrome.

genetics↗