IFT52mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome

Abstract

The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton.

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

“…The data also establish the molecular basis of SRPS type IV and demonstrate that it is allelic with SRPS type II. Previous publications of SRPS and ATD cases from the ISDR have included 22 additional families with mutations in nine ciliary genes ( DYNC2H1, WDR34, IFT52, ICK, INTU, IFT81, DYNC2LI1, IFT43 , and WDR35 ), including six genes not represented among the current set of families (Duran, et al., ; Huber et al., ; Taylor et al., ; Taylor et al., ; Toriyama et al., ; Zhang et al., ). Mutations have also been reported in families in this spectrum of disease in six additional genes, C21ORF2 (McInerney‐Leo et al., ; Wheway et al., ), TCTEX1D2 (Gholkar et al., ), IFT172 (Halbritter et al., ), KIAA0586 (Alby et al., ), CEP120 (Shaheen et al., ), or IFT122 (Walczak‐Sztulpa et al., ), bringing the number of known skeletal ciliopathy genes to twenty six.…”

“…We identified causal variants in only six out of 152 families and only two of the 14 genes ( TRAF3IP1 and IFT80 ) that encode IFT‐B components. In the total ISDR skeletal ciliopathy cohort, there was also one family with unclassified SRPS due to IFT52 mutations (Zhang et al., ) and one family each with ATD and SRPS type III due to IFT81 mutations (Duran, et al., ), so overall nine out of 175 (5%) families studied had IFT‐B defects. It is unclear why the genes encoding anterograde IFT components are less frequently mutated than retrograde molecules in the SRPS‐ATD spectrum of disease.…”

“…Mutations in all six of the genes encoding retrograde transport (IFT‐A) components ( IFT43 (Arts et al., ), WDR19 (Bredrup, et al., ), IFT122 (Walczak‐Sztulpa et al., ), TTC21B (Davis et al., ), WDR35 (Mill et al., ), and IFT140 (Perrault et al., ; Schmidts et al., )) have also been characterized in these disorders. By contrast, mutations in only a subset of the genes encoding IFT‐B complex members, IFT80 (Cavalcanti et al., ), IFT172 (Halbritter et al., ), IFT52 (Zhang et al., ), and IFT81 (Duran, et al., ), have been identified among the skeletal ciliopathies. In addition, mutations in two genes ( EVC (Ruiz‐Perez et al., ), EVC2 (Galdzicka et al., )) that encode basal body proteins, the NEK1 kinase gene (Thiel et al., ) and the gene encoding its interacting protein C21ORF2 (McInerney‐Leo et al., ; Wheway et al., ), the ICK MAP‐like kinase gene (Taylor et al., ), the INTU planar cell polarity (PCP) gene (Toriyama et al., ), the KIAA0586 (Alby et al., ) centrosomal protein gene, and the CEP120 core centriolar protein gene (Shaheen et al., ) have also been reported.…”

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

“…It is involved in anterograde transport from the base to the tip of cilia (Perrault et al., ). All six components of the IFT‐A complex have been associated with skeletal ciliopathies (Huber & Cormier‐Daire, ) and so far 4 out of 16 members of the IFT‐B complex have been associated with skeletal ciliopathies ( IFT52 , IFT80, IFT172, IFT81 ) (Beales et al., ; Duran et al., ; Halbritter et al., ; Zhang et al., ). Compound heterozygous mutation in IFT81 (p.Leu29Phe;p.Arg512* and p.Leu262*;c.1303_1305delCTT, respectively) have been shown to cause phenotypes within ATD and short‐rib polydactyly syndrome type II (Duran et al., ).…”

Genes and molecular pathways underpinning ciliopathies

“…For example, hypomorphic mutations in IFT172 result in the skeletal ciliopathies JATD and Mainzer–Saldino syndrome 128 , or VACTERL (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal and radial anomalies and limb defects) associated with hydrocephalus 129 . Mutations in IFT52 and IFT80 also cause skeletal ciliopathies 130,131 . The disruption of IFT57 is associated with OFD, as well as short stature and brachymesophalangia 132 .…”