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The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects.

ABSTRACT: The embryonic myosin isoform is expressed during fetal development and rapidly down-regulated after birth. Freeman-Sheldon syndrome (FSS) is a disease associated with missense mutations in the motor domain of this myosin. It is the most severe form of distal arthrogryposis, leading to overcontraction of the hands, feet, and orofacial muscles and other joints of the body. Availability of human embryonic muscle tissue has been a limiting factor in investigating the properties of this isoform and its mutations. Using a recombinant expression system, we have studied homogeneous samples of human motors for the WT and three of the most common FSS mutants: R672H, R672C, and T178I. Our data suggest that the WT embryonic myosin motor is similar in contractile speed to the slow type I/? cardiac based on the rate constant for ADP release and ADP affinity for actin-myosin. All three FSS mutations show dramatic changes in kinetic properties, most notably the slowing of the apparent ATP hydrolysis step (reduced 5-9-fold), leading to a longer lived detached state and a slowed Vmax of the ATPase (2-35-fold), indicating a slower cycling time. These mutations therefore seriously disrupt myosin function.

SUBMITTER: Walklate J

PROVIDER: S-EPMC4858979 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects.

Walklate Jonathan J Vera Carlos C Bloemink Marieke J MJ Geeves Michael A MA Leinwand Leslie L

The Journal of biological chemistry 20160304 19

The embryonic myosin isoform is expressed during fetal development and rapidly down-regulated after birth. Freeman-Sheldon syndrome (FSS) is a disease associated with missense mutations in the motor domain of this myosin. It is the most severe form of distal arthrogryposis, leading to overcontraction of the hands, feet, and orofacial muscles and other joints of the body. Availability of human embryonic muscle tissue has been a limiting factor in investigating the properties of this isoform and i ...[more]

PMID: 26945064

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Project description:IntroductionFreeman-Sheldon syndrome (FSS), also known as the distal arthrogryposis (DA) type 2A, is a rare congenital anomaly. We report a unique case of the DA type 2A with mixed clinical features and the unusual presentation of bilateral congenital dislocation of the knee but had unassisted stiff knee gait.Case reportA 5-year-old female child presented to the clinic with the complaint of inability to bend both knees since birth. She had an unassisted bipedal gait, but could not squat, cross-leg sit, run, and climb stairs without assistance. Her youngest brother had a similar presentation but succumbed to death at the age of 5 months due to respiratory distress. Clinical features were in the favor of FSS. Her serum creatinine kinase level was normal and the electromyography of bilateral tibialis anterior and abductor pollicis brevis was not suggestive of the myotonia. Radiograph of the skull showed cooper beaten skull appearance whereas bilateral pelvis with the hip showed following changes in the right hip; decrease femoral epiphysis height, horizontal proximal femoral physis, and the coxa brevia. She was initially managed conservatively by weekly stretching, manipulation, and casting. As a result, she could flex her knee up to 20°. Although the quadricepsplasty might be helpful for the persistent extension deformity, there was marked quadriceps weakness which could make it harder for the child to stand and walk. In addition, the abnormal muscle physiology in FSS may result in unfavorable outcomes after the surgery. Moreover, a consideration of the surgical aspect is not free of risks which include difficult endotracheal intubation, vein access, and malignant hyperthermia.ConclusionFSS is a rare congenital anomaly that should be differentiated from another syndrome of the close resemblance, Sheldon Hall syndrome and Schwartz Jampel syndrome which are other rare autosomal recessive disorders characterized by myotonia and the chondrodysplasia. Conservative management has still a role in bilateral knee involvement especially if the patient is an independent walker.

Dataset Information

The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects.

Publications

The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects.

Similar Datasets

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