Abstract
Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice.
Highlights
Arthrogryposis describes a broad range of phenotypes consisting of multiple congenital joint contractures presenting at birth [1]
Whole genome sequencing was performed on individuals with DA5, in which arthrogryposis occurs in combination with ptosis, ophthalmoplegia, and facial dysmorphism, and gain of function variants
Many techniques and organisms have been used for modeling arthrogryposis, each of which provides complementary information that is essential for understanding basic mechanisms and will yield translational benefits to human patients
Summary
DA patients are offered supportive care to improve quality of life, including occupational therapy, physical therapy, and surgery [10] While these treatments improve outcome for patients, they often fall short of complete restoration of range of motion in the joints and functionality. This strategy fails to address underlying causes for DA, such as muscle weakness and impaired neurotransmission. Conditional knockouts, while very helpful in defining gene function, rarely replicate the human phenotype in its entirety, but may be required when early lethality limits further study These methods allow researchers to design models that more accurately represent these human conditions, and replicate pathogenic effects broadly or in specific tissues. We will examine the current trajectory of DA research, and how these research strategies can help those afflicted by DA
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