Translational research in the Plain community (Amish and Mennonites)
The Plain population (Amish and Mennonites) originated from founder populations with subsequent genetic bottlenecks and genetic drift; leading to a loss of diversity and an altered genetic disease burden. The Western PA Plain people are among the least genetically characterized Plain communities in the US. A multitude of genetic diseases are characterized in the Plain population, and we aim to identify novel genetic disorders/ disease-causing variants in the Western PA Plain community through whole exome or whole genome sequencing.
Additionally, we perform functional studies to prove pathogenicity of the variants identified in addition to co-segregation analysis. This research will enable a community-centric personalized medicine approach to care based on individual genetic risk. Knowledge of genetic disorders originally developed through study of the Plain Populations, can subsequently be applied in the general population.
Understanding the pathophysiology of TANGO2 deficiency
TANGO2 deficiency is a devastating neurodevelopmental disorder caused my mutations in TANGO2 gene. Patients present with severe developmental delay, seizures, rhabdomyolysis, lactic acidosis, and hyperammonemia. However, the cellular pathophysiology of the disease remains unknow. Most proteins are transported to different cellular locations after synthesis in the endoplasmic reticulum, a process mediated by a variety of known chaperonin proteins. TANGO2 has been hypothesized to be one such protein; however, this function has been poorly studied, its transport partners are unknown, and other potential functions of TANGO2 may exist.
Our preliminary studies have shown that cultured fibroblasts from TANGO2 deficient patients exhibit mitochondrial energy dysfunction, a previously unrecognized cellular derangement. We hypothesize that this defect is related to impaired transport of nuclear encoded mitochondrial proteins to the mitochondria. The goal of this project is to understand the pathophysiology of TANGO2 induced mitochondrial energy dysfunction and the role it plays in the transport of some proteins between different organelles such as Golgi, endoplasmic reticulum and mitochondria. This is a necessary first step to developing new therapies for this disorder.