Our laboratory is interested in determining the molecular mechanisms for disease using human genetic approaches to investigate clinical phenotypes. A major focus is the molecular genetics of Charcot-Marie-Tooth (CMT) disease and related inherited demyelinating peripheral neuropathies. The predominant form of CMT results from an inherited DNA rearrangement and a gene dosage effect. The 1.5 Mb tandem CMT1A duplication arises from recombination at flanking ~24 kb repeat sequences (CMT1A-REPs). The reciprocal recombination results in a 1.5 Mb deletion and a clinically distinct dominant demyelinating neuropathy: hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A duplication and HNPP deletion document the first examples in humans of Mendelian syndromes resulting from the reciprocal products of unequal exchange involving large intrachromosomal segments. CMT1A and HNPP result from altered copy number of PMP22 and constitute an unprecedented model of phenotypic consequences resulting from a range of possible gene dosages in humans. Current efforts are focused on identifying mutations in other genes that result in inherited neuropathy phenotypes and investigating molecular mechanisms, such as nonsense-mediated decay, for genotype/phenotype correlations. To date, more than 30 CMT genes have been identified. Genes for structural proteins (PMP22, MPZ), a gap junction protein (Cx32), transcription factors (EGR2, SOX10, SIMPLE), signal transduction molecules, and proteins important for axonal transport have been associated with CMT or related neuropathy. One further focus is to investigate small molecules that may affect protein folding as a potential therapeutic approach to selected forms of neuropathy.

Additional efforts are aimed at determining the molecular mechanism for contiguous gene syndromes. An extensive clinical description is underway to study patients with deletion 17p11.2 or the Smith-Magenis syndrome (SMS). The SMS common deletion occurs by nonallelic homologous recombination (NAHR) of a flanking low-copy repeat (LCR) gene cluster (SMS-REP) and the reciprocal recombination results in duplication of this region. Results from other laboratories suggest that a similar mechanism is responsible for other interstitial microdeletion syndromes. Current efforts focus on using mouse models to delineate the gene(s) responsible for the phenotype and study the phenotypic consequences of systematic alterations in copy number for dosage sensitive genes. Studies on both CMT1A and SMS have delineated the concept of genomic disorders-structural features of the genome which can lead to DNA rearrangements and human disease traits.

Other human genetic disease gene mapping research involves collaborative efforts with Dr. Richard A. Lewis to determine the molecular genetic bases of retinopathies including Stargardt disease: Studies of Bardet-Biedl syndrome (BBS) have suggested a novel genetic mechanism we have termed "triallelic inheritance" for this genetically heterogeneous condition. In some families, a combination of three distinct alleles from two (or more) loci appear necessary and sufficient for trait manifestation. Triallelic inheritance may represent a transmission model that bridges classic Mendelian disorders with complex traits.