Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short-rib polydactyly syndrome type III phenotype

摘要

Short-rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phe-notypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short-rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short-rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule-binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubulebinding affinity of dynein. Short-rib polydactyly syndrome (SRPS) type III (OMIM 613091) is an autosomal recessive lethal skeletal dysplasia characterized by extreme narrowness of the thorax, severely shortened tubular bones with round metaphyseal ends and lateral spikes, polydactyly, and multiple anomalies of the major organs (Verma et al. 1975; Naumoff et al. 1977; Meizner and Barnhard 1995; Wu et al. 1995). SRPS type III is phenotypically and radiologically closely related to asphyxiating thoracic dystrophy (ATD; OMIM 208500), but is more severe and characterized by early prenatal expression and lethality (Ho et al. 2000). Mutations in four intraflagellar transport genes, DYNC2H1 (OMIM 603297) (Dagoneau et al. 2009; Merrill et al. 2009; Baujat et al. 2013; Schmidts et al. 2013a), IFT80 (OMIM 611177) (Beales et al. 2007; Cavalcanti et al. 2011; Baujat et al. 2013), WDR34 (OMIM 613363) (Huber et al. 2013; Schmidts et al. 2013b), and WDR60 (OMIM 615462) (McInerney-Leo et al. 2013), have been identified in both SRPS type III and ATD, suggesting that these two conditions are allelic.