Dr. Laura Ranum uses human genetics to define the molecular causes
of ataxia and myotonic muscular dystrophy (DM) and animal models
to understand how the various disease mutations her group has identified
cause muscular dystrophy and/or effects on the neurons in the brain. 

In 2001 Dr. Ranum and colleagues demonstrated that a novel form of myotonic
dystrophy is caused by a CCTG tetranucleotide expansion in intron 1 of the zinc
finger protein 9 gene. This discovery clarified previous models of DM pathogenesis
demonstrating that expansions expressed at the RNA level can be pathogenic and
cause the multisystemic features common to both diseases. Dr. Ranum’s group is
currently generating murine models of DM2 to better understand the effects of this
mutation on skeletal and cardiac muscle as well as the central nervous system and
the potential reversibility of the disease.

In 1999 the Ranum lab isolated a novel ataxia mutation for spinocerebellar ataxia
type 8 (SCA8).  An additional research focus is aimed at understanding how at the
molecular level the SCA8 repeat expansion mutation causes ataxia. A murine model
developed in the lab has a progressive and lethal neurological phenotype which
is being used to investigate the molecular mechanisms of this disorder.

Recently Dr. Ranum’s group has demonstrated that mutations in B-III spectrin
cause spinocerebellar ataxia type 5, a progressive, adult-onset, neurodegenerative
disease that causes incoordination and significant disability.  β-III spectrin is highly
expressed in cerebellar Purkinje cells and has been shown to stabilize the glutamate
transporter EAAT4 at the surface of the plasma membrane.  Dramatic differences
in two proteins important in glutamate signaling EAAT4 and GluRδ2 were found by
Western and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate
that wildtype but not mutant β-III spectrin stabilizes EAAT4 at the plasma membrane. 
Spectrin mutations are a novel cause of ataxia and neurodegenerative disease that
affect the stabilization of membrane proteins involved in glutamate signaling.


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