Article

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

Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2009; 84(4):542-9. DOI: 10.1016/j.ajhg.2009.03.015
Source: PubMed

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.

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    • "This observation extends to the craniofacial skeleton. For example, mutations in the IFT protein DYNC2H1, causes short rib polydactyly syndrome, a lethal autosomal recessive condition that features cerebral and skeletal abnormalities, such as HPE, in addition to other appendicular malformations (Dagoneau et al., 2009; Merrill et al., 2009; El Hokayem et al., 2012). Mutations in another IFT protein, IFT144, also result in craniofacial anomalies such as craniosynostosis and exencephaly, which results from deficient ciliogenesis and diminished response to upstream activation of HH signaling (Ashe et al., 2012). "
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    ABSTRACT: During craniofacial development, the Hedgehog (HH) signaling pathway is essential for mesodermal tissue patterning and differentiation. The HH family consists of three protein ligands: Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH), of which two are expressed in the craniofacial complex (IHH and SHH). Dysregulations in HH signaling are well documented to result in a wide range of craniofacial abnormalities, including holoprosencephaly (HPE), hypotelorism, and cleft lip/palate. Furthermore, mutations in HH effectors, co-receptors, and ciliary proteins result in skeletal and craniofacial deformities. Cranial suture morphogenesis is a delicate developmental process that requires control of cell commitment, proliferation and differentiation. This review focuses on both what is known and what remains unknown regarding HH signaling in cranial suture morphogenesis and intramembranous ossification. As demonstrated from murine studies, expression of both SHH and IHH is critical to the formation and fusion of the cranial sutures and calvarial ossification. SHH expression has been observed in the cranial suture mesenchyme and its precise function is not fully defined, although some postulate SHH to delay cranial suture fusion. IHH expression is mainly found on the osteogenic fronts of the calvarial bones, and functions to induce cell proliferation and differentiation. Unfortunately, neonatal lethality of IHH deficient mice precludes a detailed examination of their postnatal calvarial phenotype. In summary, a number of basic questions are yet to be answered regarding domains of expression, developmental role, and functional overlap of HH morphogens in the calvaria. Nevertheless, SHH and IHH ligands are integral to cranial suture development and regulation of calvarial ossification. When HH signaling goes awry, the resultant suite of morphologic abnormalities highlights the important roles of HH signaling in cranial development.
    Full-text · Article · Apr 2013 · Frontiers in Physiology
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    • "Thus, some retention of IFT140 activity in patients may be necessary for early embryonic survival. This observation is in agreement with observations for mutations in other genes causing phenotypes within the short rib-polydactyly spectrum [Beales et al., 2007; Dagoneau et al., 2009; Davis et al., 2011; Merrill et al., 2009; Schmidts et al., 2013]. Likewise, no significantly different clinical features could be determined between IFT140 patients with two potentially hypomorphic missense mutations and those carrying combined missense and truncating mutations. "
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    ABSTRACT: Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib polydactyly syndromes, including Jeune, Sensenbrenner and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia which play a crucial role in skeletal and chondral development. Here we identified mutations in IFT140, an IFT complex A gene, in five JATD and two MSS families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customised ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared to non-ciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under seven years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared to the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD, MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and or retinal dystrophy.
    Full-text · Article · Feb 2013 · Human Mutation
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    • "Thus, some retention of IFT140 activity in patients may be necessary for early embryonic survival. This observation is in agreement with observations for mutations in other genes causing phenotypes within the short rib-polydactyly spectrum [Beales et al., 2007; Dagoneau et al., 2009; Davis et al., 2011; Merrill et al., 2009; Schmidts et al., 2013]. Likewise, no significantly different clinical features could be determined between IFT140 patients with two potentially hypomorphic missense mutations and those carrying combined missense and truncating mutations. "

    Full-text · Article · Feb 2013 · Human Mutation
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