Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome

Abstract

The short-rib polydactyly (SRP) syndromes are a heterogeneous group of perinatal lethal skeletal disorders with polydactyly and multisystem organ abnormalities. Homozygosity by descent mapping in a consanguineous SRP family identified a genomic region that contained DYNC2H1, a cytoplasmic dynein involved in retrograde transport in the cilium. Affected individuals in the family were homozygous for an exon 12 missense mutation that predicted the amino acid substitution R587C. Compound heterozygosity for one missense and one null mutation was identified in two additional nonconsanguineous SRP families. Cultured chondrocytes from affected individuals showed morphologically abnormal, shortened cilia. In addition, the chondrocytes showed abnormal cytoskeletal microtubule architecture, implicating an altered microtubule network as part of the disease process. These findings establish SRP as a cilia disorder and demonstrate that DYNC2H1 is essential for skeletogenesis and growth.

Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish

“…4F) and were also able to exclude cd28 (supplementary material Table S3D). Because mutations in DYNC2H1 cause thoracic dysplasia and ciliary defects in humans (Dagoneau et al, 2009;Merrill et al, 2009;El Hokayem et al, 2012;Schmidts et al, 2013) we first confirmed the nonsense mutation by sequencing single WT and homozygous aa65.6 pd1086 mutant larvae (Fig. 4G).…”

Comparative genomics reveals convergent evolution between the bamboo-eating giant and red pandas

“…Among the 70 adaptively convergent genes, DYNC2H1 and PCNT are involved in limb development and their missense or null mutations result in a polydactyly phenotype and abnormal skeletogenesis in both mice and humans (25)(26)(27)(28). These findings suggest that convergent amino acid substitutions in these genes may introduce subtle changes in the functional spectrum of focal proteins and consequently contribute to pseudothumb development in both pandas.…”

“…These findings suggest that convergent amino acid substitutions in these genes may introduce subtle changes in the functional spectrum of focal proteins and consequently contribute to pseudothumb development in both pandas. The DYNC2H1 protein is a core component of the dynein complex, the motor of retrograde intraflagellar transport (IFT) during ciliogenesis (25,26). Two convergent substitutions of R3128K and K3999R were identified ( Fig.…”

“…2A) (28). It has been reported that amino acid changes in the stalk domain of DYNC2H1 affect retrograde IFT and produce abnormal primary cilia (26). Primary cilia are signal transduction organelles of the Sonic Hedgehog (SHH) signaling pathway, and abnormal cilia would inhibit the functions of GLI3, a major downstream target of the SHH pathway (25).…”

Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin

“…The IFT complexes transport proteins that are necessary for the assembly and maintenance of cilia (Ishikawa and Marshall, 2011), and also move signals between the cilium and cell body (Eguether et al, 2014;Liem et al, 2012;Liew et al, 2014;Wang et al, 2006). Mutations in IFT motors and complex proteins cause defects in ciliary assembly and function, resulting in several human diseases, including Jeune asphyxiating thoracic dystrophy, short-rib polydactyly syndrome, Mainzer-Saldino syndrome and Ellis-van Creveld syndrome (Aldahmesh et al, 2014;Beales et al, 2007;Caparrós-Martín et al, 2015;Dagoneau et al, 2009;Davis et al, 2011;Halbritter et al, 2013;Huber et al, 2013;McInerney-Leo et al, 2013;Merrill et al, 2009;Perrault et al, 2012Perrault et al, , 2015Schmidts et al, 2013Schmidts et al, , 2015.…”