Dataset Information

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

ABSTRACT: The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ?34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

SUBMITTER: Lalani SR

PROVIDER: S-EPMC4746334 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

Lalani Seema R SR Liu Pengfei P Rosenfeld Jill A JA Watkin Levi B LB Chiang Theodore T Leduc Magalie S MS Zhu Wenmiao W Ding Yan Y Pan Shujuan S Vetrini Francesco F Miyake Christina Y CY Shinawi Marwan M Gambin Tomasz T Eldomery Mohammad K MK Akdemir Zeynep Hande Coban ZH Emrick Lisa L Wilnai Yael Y Schelley Susan S Koenig Mary Kay MK Memon Nada N Farach Laura S LS Coe Bradley P BP Azamian Mahshid M Hernandez Patricia P Zapata Gladys G Jhangiani Shalini N SN Muzny Donna M DM Lotze Timothy T Clark Gary G Wilfong Angus A Northrup Hope H Adesina Adekunle A Bacino Carlos A CA Scaglia Fernando F Bonnen Penelope E PE Crosson Jane J Duis Jessica J Maegawa Gustavo H B GH Coman David D Inwood Anita A McGill Jim J Boerwinkle Eric E Graham Brett B Beaudet Art A Eng Christine M CM Hanchard Neil A NA Xia Fan F Orange Jordan S JS Gibbs Richard A RA Lupski James R JR Yang Yaping Y

American journal of human genetics 20160121 2

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation ...[more]

PMID: 26805781

Similar Datasets

Project description:Deficits in the ankle plantarflexor muscles, such as weakness and contracture, occur commonly in conditions such as cerebral palsy, stroke, muscular dystrophy, Charcot-Marie-Tooth disease, and sarcopenia. While these deficits likely contribute to observed gait pathologies, determining cause-effect relationships is difficult due to the often co-occurring biomechanical and neural deficits. To elucidate the effects of weakness and contracture, we systematically introduced isolated deficits into a musculoskeletal model and generated simulations of walking to predict gait adaptations due to these deficits. We trained a planar model containing 9 degrees of freedom and 18 musculotendon actuators to walk using a custom optimization framework through which we imposed simple objectives, such as minimizing cost of transport while avoiding falling and injury, and maintaining head stability. We first generated gaits at prescribed speeds between 0.50 m/s and 2.00 m/s that reproduced experimentally observed kinematic, kinetic, and metabolic trends for walking. We then generated a gait at self-selected walking speed; quantitative comparisons between our simulation and experimental data for joint angles, joint moments, and ground reaction forces showed root-mean-squared errors of less than 1.6 standard deviations and normalized cross-correlations above 0.8 except for knee joint moment trajectories. Finally, we applied mild, moderate, and severe levels of muscle weakness or contracture to either the soleus (SOL) or gastrocnemius (GAS) or both of these major plantarflexors (PF) and retrained the model to walk at a self-selected speed. The model was robust to all deficits, finding a stable gait in all cases. Severe PF weakness caused the model to adopt a slower, "heel-walking" gait. Severe contracture of only SOL or both PF yielded similar results: the model adopted a "toe-walking" gait with excessive hip and knee flexion during stance. These results highlight how plantarflexor weakness and contracture may contribute to observed gait patterns.

Dataset Information

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

Publications

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure