The Clinical Neurogenetics research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary movement and neuromuscular disorders. MYOFIBRILLAR MYOPATHIES: We have previously identified desmin gene as the cause of cardiac and skeletal myopathies. To-date, 45 mutations in this gene have been proven pathogenic. New studies conducted in this laboratory have shown that mutations in desmin gene caused the disease in only 62% of 147 patients with a definite diagnosis of myofibrillar myopathy we have studied over the year. The remaining 33% have now been associated with mutations in four other genes, MYOT in 28%, ZASP in 3%, CRYAB and FLNC in 1% each, and 5% of patients had mutations in more than one gene. Our analysis established sufficient clinical, electrophysiological and myopathological similarity between these diverse genetic subtypes allowing to classify them as Myofibrillar myopathies;at the same time, we uncovered substantial phenotypic distinctions between the genetically identified subtypes that should be considered in future studies of disease pathogenesis, and used for optimization of subtype-specific treatments and management. CHARCOT-MARIE-TOOTH DISEASE TYPE 2D AND SPINAL MUSCULAR ATROPHY TYPE V: We have previously identified glycyl-tRNA synthetase (GARS) gene mutations as the cause of autosomal dominant motor distal neuronopathy/axonopathy. We now tested a group of sporadic patients with a presumptive diagnosis of CMT2D for mutations in GARS gene, and, in addition, conducted a study of possible GARS involvement in patients with juvenile-onset muscular atrophy of the distal upper extremity classified as Hirayamas disease. Our preliminary conclusion was that GARS was not a factor in the etiology of Hirayamas disease in this specific cohort. CHROMOSOMAL MAPPING OF GENES CAUSING ESSENTIAL TREMOR: Essential tremor is the most common neurological disease affecting 4 to 6% of people at the age older than 40. Previously, we reported a new promising locus on chromosome 6p23 in two American families. We have now tested for mutations 14 candidate genes located in the 600-kB linked region. Some sequence variants are under study. Two other families, American and Spanish, show linkage to a different locus on chromosome 11p15 with LOD score of 2.45 spanning 9 cM, which suggests that more than one or even two genes are likely to be responsible for familial Essential tremor. High density single nucleotide polymorphism genotyping did not improve the LOD score but was able to narrow the linked region to 3.5 cM. We tested candidate genes in this region, which are functionally relevant. We sequenced coding regions of SYT8 and KCNQ1DN genes and demonstrated that RNA expression level of another candidate gene, DRD4, was increased in a muscle biopsy sample from one of the patients. We are planning to follow up on these results by examining more genes and additional tissue samples from affected family members.
| Kley, Rudolf A; van der Ven, Peter F M; Olive, Montse et al. (2013) Impairment of protein degradation in myofibrillar myopathy caused by FLNC/filamin C mutations. Autophagy 9:422-3 |
| Toro, Camilo; Olive, Montse; Dalakas, Marinos C et al. (2013) Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. BMC Neurol 13:29 |
| Fürst, Dieter O; Goldfarb, Lev G; Kley, Rudolf A et al. (2013) Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol 125:33-46 |
| Sambuughin, Nyamkhishig; Swietnicki, Wieslaw; Techtmann, Stephen et al. (2012) KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase. Biochem Biophys Res Commun 421:743-9 |
| Tasca, Giorgio; Odgerel, Zagaa; Monforte, Mauro et al. (2012) Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia. Muscle Nerve 46:275-82 |
| Liberski, Pawel P; Sikorska, Beata; Lindenbaum, Shirley et al. (2012) Kuru: genes, cannibals and neuropathology. J Neuropathol Exp Neurol 71:92-103 |
| Maddison, Paul; Damian, Maxwell S; Sewry, Caroline et al. (2012) Clinical and myopathological characteristics of desminopathy caused by a mutation in desmin tail domain. Eur Neurol 68:279-86 |
| Odgerel, Zagaa; Lee, Hee S; Erdenebileg, Narnygerel et al. (2012) Genetic variants in potassium channels are associated with type 2 diabetes in a Mongolian population. J Diabetes 4:238-42 |
| Kley, Rudolf A; Serdaroglu-Oflazer, Piraye; Leber, Yvonne et al. (2012) Pathophysiology of protein aggregation and extended phenotyping in filaminopathy. Brain 135:2642-60 |
| Olivé, Montse; Odgerel, Zagaa; Martínez, Amaia et al. (2011) Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy. Neuromuscul Disord 21:533-42 |
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