Dolichols are long-chain isoprenoid products of the mevalonate pathway that act in the initial steps of glycosylation of proteins and certain lipids. Recently, inherited disorders of dolichol synthesis or utilization have been discovered. Patients present with variable multiorgan symptoms and exhibit defective lipid and protein glycosylation. Few patients have been identified and little or nothing is known about the longitudinal natural history these diseases. Although many patients have underglycosylated proteins, a biomarker that correlates with disease severity or can be used for monitoring disease progression has not been identified. Further, effective therapy for the isoprenoid diseases does not yet exist. Based on the known dolichol synthesis pathway, it is likely that new diseases of dolichol metabolism are waiting to be identified. We propose to define the natural history of inborn errors of dolichol metabolism by systematically characterizing their clinical features and documenting how they change over time. Comprehensive clinical evaluations will be performed every year to determine the frequency and variability of symptoms. We will search for the most useful biomarkers that correlate with disease severity and progression. For those patients lacking a DNA diagnosis, we will perform mutation analysis to characterize the molecular defects in the known dolichol genes and search for additional new dolichol-related disease genes using whole exome sequencing. In this fashion, we will achieve new insight into the clinical features and natural history of these rare diseases.

Public Health Relevance

Owing to the rare nature of dolichol metabolim diseases and their recent discovery, the proposed studies to characterize their clinical features and define their natural history are highly relvant for these diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54HD061939-06
Application #
8936526
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Krotoski, Danuta
Project Start
2014-09-04
Project End
2019-08-31
Budget Start
2014-09-04
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$179,999
Indirect Cost
$40,672
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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