The genetic work-up of arthrogryposis is challenging due to the diverse clinical and molecular etiologies. We report a-183/12-year-old boy, from a 2nd degree consanguineous family, who presented at 36/12 years with hypotonia, distal laxity, contractures, feeding difficulties at birth. He required surgery for progressive scoliosis at 16 years of age, and walked independently since then with an unstable gait and coordination defects. His latest examination at 18 years of age revealed a proprioceptive defect and loss-of-joint position sense in the upper limbs. Somatosensory evoked potentials supported bilateral involvement of dorsal column-medial lemniscal sensory pathways and nerve conduction studies revealed a mild axonal neuropathy. Muscle biopsy showed myopathic changes with neonatal myosin expression. Mendeliome sequencing led to the discovery of a recessive stop mutation in piezo-type mechanosensitive ion channel component 2 (PIEZO2, NM_022068, c.1384C>T, p.R462*). PIEZO2 is a nonselective cation channel, expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs. Dominant PIEZO2 mutations were described in patients with distal arthrogryposis type 5 and Marden–Walker syndrome. Sensory ataxia and proprioception defect with dorsal column involvement together with arthrogryposis, myopathy, scoliosis and progressive respiratory failure may represent a distinct clinical phenotype, and indicate recessive mutations in PIEZO2.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hall, J. G. Arthrogryposis multiplex congenita: etiology, genetics, classification, diagnostic approach, and general aspects. J. Pediatr. Orthop. B 6, 159–166 (1997).
DeMyer, W. & Baird, I. Mortality and skeletal malformations from amniocentesis and oligohydramnios in rats: cleft palate, clubfoot, microstomia, and adactyly. Teratology 2, 33–37 (1969).
Swinyard, C. A. Concepts of multiple congenital contractures (arthrogryposis) in man and animals. Teratology 25, 247–258 (1982).
Hall, J. G. Arthrogryposis (multiple congenital contractures): diagnostic approach to etiology, classification, genetics, and general principles. Eur. J. Med. Genet. 57, 464–472 (2014).
Fazeli, W., Karakaya, M., Herkenrath, P., Vierzig, A., Dotsch, J., von Kleist-Retzow, J. C. et al. Mendeliome sequencing enables differential diagnosis and treatment of neonatal lactic acidosis. Mol. Cell. Pediatr. 3, 22 (2016).
Coste, B., Houge, G., Murray, M. F., Stitziel, N., Bandell, M., Giovanni, M. A. et al. Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of distal arthrogryposis. Proc. Natl Acad. Sci. USA 110, 4667–4672 (2013).
McMillin, M. J., Beck, A. E., Chong, J. X., Shively, K. M., Buckingham, K. J., Gildersleeve, H. I. et al. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am. J. Hum. Genet. 94, 734–744 (2014).
Okubo, M., Fujita, A., Saito, Y., Komaki, H., Ishiyama, A., Takeshita, E. et al. A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation. Ame. J. Med. Geneti. A 167A, 1100–1106 (2015).
Coste, B., Mathur, J., Schmidt, M., Earley, T. J., Ranade, S., Petrus, M. J. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).
Cahalan, S. M., Lukacs, V., Ranade, S. S., Chien, S., Bandell, M. & Patapoutian, A. Piezo1 links mechanical forces to red blood cell volume. eLife 4 (2015).
Ranade, S. S., Syeda, R. & Patapoutian, A. Mechanically activated ion channels. Neuron 87, 1162–1179 (2015).
Retailleau, K., Duprat, F., Arhatte, M., Ranade, S. S., Peyronnet, R., Martins, J. R. et al. Piezo1 in smooth muscle cells is involved in hypertension-dependent arterial remodeling. Cell Rep. 13, 1161–1171 (2015).
Woo, S. H., Lukacs, V., de Nooij, J. C., Zaytseva, D., Criddle, C. R., Francisco, A et al. Piezo2 is the principal mechanotransduction channel for proprioception. Nat. Neurosci. 18, 1756–1762 (2015).
Dubin, A. E., Schmidt, M., Mathur, J., Petrus, M. J., Xiao, B., Coste, B. et al. Inflammatory signals enhance piezo2-mediated mechanosensitive currents. Cell Rep. 2, 511–517 (2012).
Chung, M. K., Park, J., Asgar, J. & Ro, J. Y. Transcriptome analysis of trigeminal ganglia following masseter muscle inflammation in rats. Mol. Pain (e-pub ahead of print 4 October 2016; doi:10.1177/1744806916668526).
Yang, H., Liu, C., Zhou, R. M., Yao, J., Li, X. M., Shen, Y. et al. Piezo2 protein: a novel regulator of tumor angiogenesis and hyperpermeability. Oncotarget 7, 44630–44643 (2016).
Chesler, A. T., Szczot, M., Bharucha-Goebel, D., Ceko, M., Donkervoort, S., Laubacher, C. et al. The role of PIEZO2 in human mechanosensation. N. Engl. J. Med. 375, 1355–1364 (2016).
Coste, B., Xiao, B., Santos, J. S., Syeda, R., Grandl, J., Spencer, K. S. et al. Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483, 176–181 (2012).
Ge, J., Li, W., Zhao, Q., Li, N., Chen, M., Zhi, P. et al. Architecture of the mammalian mechanosensitive Piezo1 channel. Nature 527, 64–69 (2015).
Mahmud, A. A., Nahid, N. A., Nassif, C., Sayeed, M. S., Ahmed, M. U., Parveen, M. et al. Loss of the proprioception and touch sensation channel PIEZO2 in siblings with a progressive form of contractures. Clin. Genet. (e-pub ahead of print 8 September 2016; doi:10.1111/cge.12850).
We acknowledge our patient and his parents. This work was supported by Muscular Dystrophy Association, USA, and Deutsche Forschungsgemeinschaft, Germany grants to Dr SC.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Journal of Human Genetics website
About this article
A hydrophobic gate in the inner pore helix is the major determinant of inactivation in mechanosensitive Piezo channels
International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita
American Journal of Medical Genetics Part C: Seminars in Medical Genetics (2019)
Progrediente Dysarthrie, Ataxie, schmerzhafte Dysästhesien der Beine und Gedächtnisstörung – was war die Ursache?
Neuromuscular Disorders (2019)
American Journal of Medical Genetics Part A (2019)