Project Summary/Abstract
Relatively little is known about SMARD1 and CMT2S and the disease-causing gene IGHMBP2 as it relates to
disease development. Therapeutic options are, at best, minimal as no approved drugs exist. The objective of
this project is to understand the consequences of disease-causing mutations in IGHMBP2 that result in SMA
with Respiratory Distress (SMARD1) or Charcot Marie Tooth Type 2S (CMT2S). Towards this goal, we have
generated six Ighmbp2 mouse models that are based on patient mutations in IGHMBP2. These models represent
the first, patient-based models of SMARD1 and CMT2S. Importantly, we demonstrate that each mutation thus
far studied demonstrates distinct disease phenotypes.
These investigations are designed to further our understanding of IGHMBP2 and its functional significance
in disease development by utilizing the Ighmbp2 mouse models and complementary approaches: genetics and
biochemistry. Aim I of this proposal examines the phenotypic and molecular changes that result from Ighmbp2
mutations R604X and H922Y and the effect of these mutations on disease progression and therapeutic efficacy.
Examining the similarities and differences between these mutations should provide valuable information towards
what molecular alterations result in the more severe SMARD1 or less severe CMT2S. Therapeutic studies
proposed will help us understand what aspects of disease pathology are altered and to what extent. Aim II utilizes
biochemistry to investigate how these IGHMBP2 mutations effect IGHMBP2 function and the association of
proteins in IGHMBP2 pathways. RNA and protein stability, protein binding affinity, ATPase and helicase activity
and processivity for these mutants will be examined in the presence of absence of ABT1, a protein that binds
IGHMBP2 and increases IGHMBP2 ATPase and helicase activity and processivity. It will be important to
determine how each of these mutations alter IGHMBP2 biochemical function and how altered IGHMBP2
biochemical function relates to disease. Our previous studies suggest that IGHMBP2-ABT1 function in 47S pre-
rRNA processing; Aim III expands on these studies. Our laboratory has developed reagents aimed at addressing
IGHMBP2-ABT1 function in neuronal and non-neuronal contexts. 47S pre-rRNA processing will be examined in
wild type and mutant contexts to determine whether and to what extent processing is altered. We will also ask
whether any processing defects can be eliminated following therapeutic delivery of IGHMBP2 or ABT1.
Each Aim of this proposal should provide independent relevant information towards understanding disease
development and progression, IGHMBP2 biological processes and targets for therapeutic development.
Determining the functional differences between IGHMBP2 mutations that result in SMARD1 versus CMT2S has
important therapeutic implications since a subtle increase in functionality can have profound clinical implications.
This proposal is a natural collaboration of MU investigators within molecular biology and neurodegenerative
fields. Each investigator provides their own unique expertise towards the successful completion of these Aims.
