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Abstract Details

Mechanism of Disease in Novel Dominant Skeletal and Cardioskelatal Titinopathies
Neuromuscular and Clinical Neurophysiology (EMG)
P10 - Poster Session 10 (5:30 PM-6:30 PM)
1-002

To investigate the mechanism of disease in probands affected with novel skeletal myopathy phenotypes associated with dominant truncating variants in TTN (TTNtv).
Currently, two dominant skeletal titinopathies are known, tibial muscular dystrophy (TMD) and hereditary myopathy with early respiratory failure (HMERF), caused by an 11-bp insertion/deletion in exon 363 and missense variants in exon 344, respectively.  We have identified novel skeletal and cardioskeletal phenotypes segregating in families with heterozygous TTNtv affecting the I-, A- or M-bands. 
We performed needle biopsies of the tibialis anterior in 5 patients and 3 controls.  Transcript, Western blot and muscle fiber mechanical studies were performed. 
In one individual with a cardioskeletal phenotype and a heterozygous deletion of exons 346-362, Western blot analysis identified normal full-length titin and a truncated titin.  The truncated protein ran as a ~3.3 MDa protein and contained full-length titin’s N-terminus but not full-length titin’s C-terminus.  Muscle fiber mechanical studies suggests that type I fibers have higher passive specific force (force normalized to fiber cross-sectional area) compared to controls and fast fibers have lower passive specific force.  In three individuals with cardioskeletal phenotypes and TTNtvs in the A-band (p.Arg25573* or p.Leu26598*), and in one individual with a skeletal phenotype and a TTNtv of the I-band (p.Ser9675*) Western blot analysis identified only normal titin and mechanical studies did not identify differences in passive specific force, suggesting these TTNtvs result in nonsense-mediated decay. RNAseq studies are underway.  Detailed clinical, genetic and muscle data will be presented.

 
We identified novel skeletal and cardioskeletal titinopathy phenotypes associated with TTNtv.  Preliminary data suggests that more than one disease mechanism may underlie these conditions.  Truncations affecting the I- and A-bands may result in nonsense-mediated decay, whereas distal A- and M-band truncations may result in abnormal titin protein products and function.
Authors/Disclosures
Jennifer A. Roggenbuck, MS, CGC (Ohio State University)
PRESENTER 		The institution of Ms. Roggenbuck has received research support from Packard Foundation.
No disclosure on file
Kelly Rich, MS, CGC Ms. Rich has nothing to disclose.
No disclosure on file
William D. Arnold, MD Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for La Hoffmann Roche. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cadent Therapeutics . Dr. Arnold has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Arnold has received research support from NIH. The institution of Dr. Arnold has received research support from NMD Pharma. The institution of Dr. Arnold has received research support from Gilead Sciences. The institution of Dr. Arnold has received research support from CureSMA. Dr. Arnold has received intellectual property interests from a discovery or technology relating to health care.
No disclosure on file