GENE DISCOVERY FOR RARE MENDELIAN DISEASES: DISORDERS OF THE TTT COMPLEX AND DISORDERS PRESENTING AS VERY EARLY ONSET INFLAMMATORY BOWEL DISORDERS
Embargo until
2022-05-01
Date
2017-11-22
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Johns Hopkins University
Abstract
Gene discovery for Mendelian disorders has witnessed tremendous advances with the development of whole exome sequencing technology and in vitro disease modeling methods in patient-derived cells and mouse models. As part of the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) I have applied these techniques to look for the responsible genes and variants focusing on disorders for which the disease gene yet to be discovered.
In the TTT complex disorders, I studied nine affected individuals from four families with intellectual disability (ID), neurological and congenital abnormalities associated with compound heterozygous loss of function variants in TELO2, which encodes one of 3 components of the TTT complex. This heterotrimeric complex is thought to function by interacting with HSP90 and the R2TP complex to catalyze the maturation of members of the Phosphatidylinositol 3-kinase-related protein kinases (PIKKs) proteins. In patient fibroblasts, I found the compound heterozygous mutations in TELO2 reduced steady state levels of TELO2 and the other two components of the TTT complex, namely TTI1 and TTI2. However, in assays of several PIKK-mediated cellular functions, I found no discernible abnormalities. I hypothesized that stressing these cellular functions might bring out a latent abnormality of PIKK function. I showed that inhibition of Hsp90 activity in cultured fibroblasts by adding 17AAG to the medium (1 μM), resulted in a substantial reduction of the steady state levels of 2 of the PIKKS (ATM and PRKDC) in patient cells but not in those of controls. This observation suggests that residual TTT complex activity maintains adequate PIKK function at baseline conditions but is not adequate when the system is stressed. To determine if cell types more directly related to the clinical phenotype might exhibit a more profound deficit in PIKK function, I generated and characterized patient iPS cell lines from two compound heterozygous TELO2 (C367F/D720V and Q172X/D720V) patients and a heterozygous carrier of D720V/+. In these cells, however, I found no significant defects in the cell proliferation rate (largely a test of proliferation function of neuron stem cells) between patient and unrelated healthy control neuron progenitor cells. My results suggest that these TELO2 missense variants result in loss-of-function of TELO2, perturb TTT complex stability and cause a newly recognized autosomal recessive syndromic form of ID. The pathophysiologic mechanism(s) by which this happens remains uncertain.
In a second project, I searched for monogenic etiologies in a cohort of 18 very early onset of inflammatory diseases (VEOIBD) probands. Of these, I found that 8 of 18 had variants in genes already known to cause disorders with VEOIBD as part of the phenotype. In 12 probands with variants in known IBD associated genes, I identified possible AR (IFIH1) and X-linked (CNGA2) examples of VEOIBD cases.
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Keywords
TELO2, very early onset of inflammatory diseases (VEOIBD)