[Show abstract][Hide abstract] ABSTRACT: MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.
[Show abstract][Hide abstract] ABSTRACT: Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
[Show abstract][Hide abstract] ABSTRACT: Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy, frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy [VCPDM]), has been mapped to chromosome 5q31 in a North American pedigree. Here, we report the identification of a second large VCPDM family of Bulgarian descent and fine mapping of the critical interval. Sequencing of positional candidate genes revealed precisely the same nonconservative S85C missense mutation affecting an interspecies conserved residue in the MATR3 gene in both families. MATR3 is expressed in skeletal muscle and encodes matrin 3, a component of the nuclear matrix, which is a proteinaceous network that extends throughout the nucleus. Different disease related haplotype signatures in the two families provided evidence that two independent mutational events at the same position in MATR3 cause VCPDM. Our data establish proof of principle that the nuclear matrix is crucial for normal skeletal muscle structure and function and put VCPDM on the growing list of monogenic disorders associated with the nuclear proteome.
The American Journal of Human Genetics 05/2009; 84(4):511-8. DOI:10.1016/j.ajhg.2009.03.006 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Corticobasal ganglionic degeneration (CBGD) is a progressive neurological disorder characterized by gradual nerve cell loss and atrophy of the cerebral cortex and basal ganglia. Symptoms of the disorder include verbal apraxia and language disturbances along with bradykinesia and rigidity. There have been no reports to date of acquired or neurogenic stuttering associated with CBGD. We describe a patient whose initial symptom of CBGD was stuttering which worsened as her disease progressed. Neuroimaging including PET scans revealed poor metabolic functioning of the right basal ganglia. This finding, along with bilateral atrophy of the frontal and parietal lobes likely contributed to the disturbance of motor sequencing skills and led to the development and worsening of stuttering, apraxia of speech and swallowing, and eventual aphasia and cognitive decline. We suggest that neurogenic stuttering may be an additional symptom of CBGD.
Journal of Neurolinguistics 01/2009; 22(1):83-90. DOI:10.1016/j.jneuroling.2008.06.003 · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.
The American Journal of Human Genetics 01/1999; 63(6):1732-42. DOI:10.1086/302166 · 10.93 Impact Factor