CODAS syndrome is a multi-system developmental disorder characterized by intellectual disability, cataracts, and abnormalities in dentition, hearig and skeletal structure. CODAS is an acronym for cerebral, ocular, dental, auricular and skeletal anomalies. Using whole exome analysis and direct genomic sequencing, we recently demonstrated that mutations in the LONP1 gene are associated with CODAS syndrome. LONP1 encodes mitochondrial Lon, which is an ATP-dependent protease, a chaperone and a DNA-binding protein. Lon binds directly to DNA and RNA, and is required for the maintenance and expression of mitochondrial DNA (mtDNA). As mtDNA encodes essential subunits of the oxidative phosphorylation system, changes in Lon function at the mitochondrial genome will impact cellular energetics and cell survival. Our published and unpublished findings demonstrate that the majority of LonCODAS mutations cluster within the AAA+ domain of Lon, which mediates DNA- and RNA- binding as well as ATP hydrolysis. This project focuses on the direct and specific role of Lon in mitochondrial gene expression (i.e. transcription and translation). The results obtained will provide key mechanistic insights into how Lon dysfunction in these processes contributes to the pathophysiology of CODAS syndrome. In addition, the discovery that CODAS syndrome is linked to naturally occurring mutations in mitochondrial Lon, provides a unique and powerful opportunity to elucidate the diverse functions of this multi-functional enzyme in both human health and common disease processes such as neurodegeneration, oncogenesis, cardiac disease as well as aging.

Public Health Relevance

CODAS syndrome is a multi-system developmental disorder characterized by mental retardation/intellectual disability, cataracts, and abnormalities in dentition, hearing and skeletal structure. Recent genetic studies show that CODAS syndrome is linked to mutations in the LONP1 gene, which encodes the mitochondrial Lon protease. Our project aims at elucidating the mitochondrial dysfunctions that result from CODAS mutations in Lon.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD083916-02
Application #
9187845
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Krotoski, Danuta
Project Start
2015-12-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rutgers University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103