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Introduction
Asphyxiating thoracic dystrophy or Jeune syndrome (Jeune asphyxiating thoracic dystrophy (JATD); MIM 208500), first described in 1955, 1 is a rare genetically heterogeneous disorder characterised by skeletal anomalies, primarily shortened ribs and limbs, brachydactyly and polydactyly. Constriction of the thoracic cage is associated with recurrent respiratory infections in particular in neonates and infants, and in 60% of cases with lethal respiratory distress. 2 Up to 30% of JATD patients also develop end stage renal disease, 3 with hepatic fibrosis and retinal involvement reported less frequently. 4 5 JATD is a member of the family of skeletal 'ciliopathies', disorders associated with dysfunction of primary cilia, classified as one of the six short-rib polydactyly syndrome (SRPS) disorders. 6 7 JATD along with Ellis-van Creveld syndrome is an SRPS compatible with life, rather than one of the four lethal SRPS subtypes (SRPS I-IV). 7 In addition, JATD is both phenotypically as well as genetically related to Sensenbrenner syndrome (Cranioectodermal dysplasia; MIM 218330) 8 and Mainzer-Saldino syndrome (Conorenal syndrome; MIM 266920). 9
Mutations in several different genes cause JATD. These genes, IFT80 , 10 TTC21B/IFT139 , 11 IFT140 , 9 12 WDR19/IFT144 8 and DYNC2H1 13 all encode proteins that participate in ciliary intraflagellar transport (IFT), an evolutionarily conserved process which is essential for ciliogenesis and governs a variety of important cell signalling events that are key to normal human development. 14 15 In IFT, two protein complexes IFT-A and IFT-B are bidirectionally transported in cilia by molecular motors, along with essential ciliary cargos. 16 17 The IFT80 protein is part of the IFT-B particle that consists of at least 14 proteins, which in association with kinesin-2 motors drives anterograde transport from the ciliary base to the tip while IFT139, IFT140 and IFT144 are all part of the IFT-A particle that consists of six proteins and in association with the cytoplasmic IFT dynein-2/1b motor drives retrograde transport from the ciliary tip to the base. 17-19 The other three IFT-A members, IFT122 , IFT43 and WDR35 , are mutated in Sensenbrenner syndrome. 20-22 Similarly, IFT144 and IFT80 are also mutated in overlapping milder syndromes and in more severe type III short-rib polydactyly. 8 23 IFT140 mutations were recently described in Mainzer-Saldino syndrome patients, and a subset of JATD...