The purpose of this research program is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. Specific research accomplishments in the past year include (1) identification of a novel ataxia telangestasia mutation in Mali, (2) identification of mutations in C19orf12 in patients with hereditary spastic paraplegia (SPG43), (3) identification of mutation in AIFM1 in patients with Cowchock syndrome (CMTX4), (4) development of new guidelines for genetic diagnosis of Charcot-Marie-Tooth disease, and (5) identification of a sequence variant in histidine aminoacyl tRNA synthetase (HARS) in a patient with axonal neuropathy. Ataxia telangiectasia is a rare, autosomal recessive disorder of childhood characterized by progressive cerebellar ataxia, telangiectasia, and immune defects, and caused by mutations in the ATM gene. The disease has been reported worldwide, but reports from Africa are rare and often limited to clinical description. We described a Malian family with parental consanguinity and three out of ten children presenting with cerebellar symptoms. Genetic analysis of the ATM gene identified a novel homozygous single nucleotide substitution predicting the amino acid substitution V2662D. The V2662 residue lies in a predicted ATP binding domain and is conserved across a broad range of vertebrate species. In addition, this acid change was not found in ethnically matched controls, suggesting that the mutation is likely deleterious. Charcot Marie Tooth disease (CMT) encompasses the inherited peripheral neuropathies. While four genes have been found to cause over 90% of genetically identifiable causes of CMT (PMP22, GJB1, MPZ, MFN2), at least 51 genes and loci have been found to cause CMT when mutated, creating difficulties for clinicians to find a genetic subtype for families. We described the classic features of CMT and the characteristic features of the most common subtypes of CMT, as well as methods for narrowing down the possible subtypes. Psychosocial concerns particular to the CMT population were identified. The result was an inclusive publication for CMT-specific genetic counseling. We identified the genetic basis for SPG43, a form of progressive hereditary spastic paraplegia we previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (A63P) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (G66del). Haplotype analysis revealed that the A63P mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. Cowchock syndrome (CMTX4) is a slowly progressive X-linked recessive disorder with axonal neuropathy, deafness, and cognitive impairment. The disease locus was previously mapped to an 11 cM region at chromosome Xq24-q26. Exome sequencing of an affected individual from the originally described family identified a missense change (E493V) in apoptosis inhibitory factor (AIFM1). The change is at a highly conserved residue and cosegregated with the phenotype in the family. AIF is an FAD-dependent NADH oxidase that is imported into mitochondria. With apoptotic insults, a N-terminal transmembrane linker is cleaved off, producing a soluble fragment that is released into the cytosol and then transported into the nucleus, where it triggers caspase-independent apoptosis. Another AIFM1 mutation, R201del, has recently been associated with severe mitochondrial encephalomyopathy in two infants by impairing oxidative phosphorylation. The E493V mutation we found alters the redox properties of the AIF protein and results in increased cell death via apoptosis, withhout affecting the activity of the respiratory chain complexes. Our findings expand the spectrum of AIF-related disease and provide insight into the effects of AIFM1 mutations. Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. We presented results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (R137G) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, R137G HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy.

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Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya et al. (2015) Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability. Hum Mutat 36:48-56
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