Clinical genetics and pathobiology of ciliary chondrodysplasias

Abstract

Ciliary chondrodysplasias represent a heterogenous group of rare, nearly exclusively autosomal recessively inherited developmental conditions. While the skeletal phenotype, mainly affecting limbs, ribs and sometimes the craniofacial skeleton, is predominant, extraskeletal disease affecting the kidneys, liver, heart, eyes and other organs and tissues is observed inconsistently. Significant lethality, resulting from cardiorespiratory failure due to thoracic constriction as well as from renal and hepatic insufficiency or primary cardiac failure due to congenital heart disease, is observed with these conditions. The underlying genetic defects as well as developmental biology and cell biology work undertaken using animal model systems, suggest that these rare conditions result from ciliary malfunction. The skeletal phenotype is believed to result from imbalances in the hedgehog signaling pathway that normally occurs in functional cilia in chondrocytes. Although phenotypes have been historically distinguished based on clinical features into short-rib polydactyly syndrome, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia), oral-facial-digital syndrome and Ellis-van Creveld syndrome, recent research suggests that there is significant genetic as well as phenotypic overlap between the conditions. This review discusses ciliary chondrodysplasias from phenotypic hallmarks to clinical management and summarizes progress in identification of the underlying molecular mechanisms as well as potential future therapeutic perspectives.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome

“…These features are reminiscent of the spectrum of SRPII and SRPIV. 1,18,19 Thus, fetuses and individuals reported in this study all display lethal phenotypes consistent with a hedgehogsignaling defect and similar to the phenotype described Mutant Cells (A) KIAA0586 mutant fibroblasts from subject II:2 in family 2 showed an altered response to smoothened agonist (SAG; sc-202814, Santa Cruz; 5 mM for 18 hr), given that they induced less GLI1 and PTCH1 expression than did control cells. Primers used for real-time qRT-PCR are listed in Table S2.…”

Biallelic mutations in DYNC2LI1 are a rare cause of Ellis‐van Creveld syndrome

“…DYNC2LI1 is a widely expressed gene coding a component of the intraflagellar transport‐related dynein‐2 complex, a machinery mediating retrograde traffic along the cilium, and whose function is required for cilium assembly and function, including signal transduction . This complex is composed of at least 5 components, including DYNC2H1 (MIM 603297), WDR34 (MIM 515633) and WDR60 (MIM 615462), whose coding genes are mutated in SRTDs with or without polydactyly . Among these disorders, features differentiating the individual nosologic entities are the variable presence of craniofacial, ocular, renal, hepatic and cardiac malformations.…”

Primary ciliary dyskinesia and associated sensory ciliopathies

“…Cranioectodermal dysplasia, Sensenbrenner syndrome, short-rib polydactyly, and Jeune asphyxiating thoracic dystrophy are another group of primary ciliopathies associated with skeletal dysplasia that affects the ribs cage leading to respiratory compromise [51]. These syndromes are collectively known as short-rib thoracic dysplasia, and are related to gene mutations that interfere with intraflagellar transport in primary cilia.…”