Neurogenetics Research Lab

Our work in the Neurogenetics Research Lab is focused on understanding the molecular mechanisms underlying the pathogenesis of human leukodystrophies, which are diseases of the white matter (myelin) of the central nervous system. A primary focus is on Pelizaeus-Merzbacher Disease (PMD) and spastic paraplegia 2 (SPG2), X-linked disorders of myelin formation.

These diseases are caused by several kinds of mutations of the gene for the most abundant protein of myelin, the proteolipid protein 1 gene (PLP1). PMD and SPG2 actually represent a spectrum of disease severities from mild SPG2, which is characterized by hypomyelination and spastic paraparesis, to severe forms of PMD, characterized by almost complete absence of white matter and severe quadriparesis.

Other classic symptoms of PMD include nystagmus, hypotonia, cognitive impairment, head titubations, and ataxia. Since PMD/SPG2 is an X-linked recessive disorder, it predominantly affects males, but female carriers may manifest symptoms of the disease, usually in its milder forms.

The diagnostics lab is the only one in the United States and one of two in the world offering molecular diagnostics for both mutation and duplication of the gene that causes this devastating disease.

One of our research interests is to improve the molecular diagnostics of PMD by refining the molecular techniques. Other research projects are focused on understanding the molecular mechanisms underlying the pathogenesis of PMD.

Learn More About the PMD Foundation

Main Interests

In the Neurogenetics Research Laboratory, we are examining the molecular mechanisms involved in two kinds of genetic defects: (1) mutations that may cause alterations in splicing and (2) genomic rearrangements in and around the PLP1 locus, the most common of which is duplication. The results of our studies will allow improved clinical and molecular diagnosis and genetic counseling, which should help decrease the incidence of these devastating diseases. We will gain insights into the mechanisms of the disease processes, thereby aiding in the development of effective strategies for therapy. In addition, what we learn about PLP1 and its expression has broad implications for other dysmyelinating and demyelinating diseases such as cerebral palsy and multiple sclerosis.

Most known disease-causing mutations of PLP1 are located in exons and affect the amino acid sequence of the PLP1 protein, but we have found that about 20 percent of PLP1 mutations, some of which are in introns, cause disease by affecting splicing of PLP1. Of particular interest to us are mutations that differentially affect the amounts of alternatively spliced mRNA products of the gene. We are using a cell culture system and a transgenic mouse model to study the effects of these mutations and to test a potential therapeutic approach.

Supported by a grant from the NIH, we are investigating the molecular characteristics of duplications and other copy number variability in and around the PLP1 locus in a large cohort of patients using quantitative PCR, array comparative genomic hybridization (aCGH), and fluorescent in situ hybridization (FISH). These characteristics include the size and orientation of the duplication, the location of the endpoints, and the sequence at abnormal junctions formed by the rearrangements. These studies will help us understand the mechanisms whereby duplications are generated.

We have generated a mouse model of the PMD duplication. The duplication in this model is similar to those in human PMD patients in size and includes other genes in the vicinity of PLP1, as do human duplications. Supported by a grant from the NIH, we are using our model to determine how duplication leads to disruption of the myelin program in males and compensatory skewing of the X-chromosome inactivation pattern in females.

We are working with the Nemours Molecular Diagnostics Lab to improve the diagnostics of leukodystrophies by refining molecular diagnostic techniques and adding new tests. An estimated 5 to 20 percent of patients with clinical findings consistent with PMD do not have a duplication or a mutation in of PLP1, so we are also identifying other disease-causing loci and setting up new diagnostic tests.