Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

Durán, Iván; Taylor, S. Paige; Zhang, Wenjuan; Martı́n, Jorge; Qureshi, Faisal; Jacques, Suzanne M.; Wallerstein, Robert; Lachman, Ralph S.; Nickerson, Deborah A.; Bamshad, Michael J.; Cohn, Daniel H.; Krakow, Deborah

doi:10.1186/s13630-017-0051-y

Cited by 27 publications

(35 citation statements)

References 43 publications

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“…Mutation frequencies are denoted with the number of circles, and the mutation types are distinguished with colors as described in Figure 1. The figure includes 10 mutations from seven previously published cases with mutations in these genes (Duran et al, 2017;Huber et al, 2013). Conserved protein domain regions were identified using the UniProt and InterPro Websites F I G U R E 4 Radiographic phenotype of the probands with EVC and EVC2 mutations.…”

Section: Evc and Evc2 Mutations Can Results In Severe Skeletal Abnormamentioning

confidence: 99%

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

et al. 2017

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Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes.The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

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Section: Evc and Evc2 Mutations Can Results In Severe Skeletal Abnormamentioning

confidence: 99%

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

et al. 2017

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“…Defects in IFT often cause abnormalities in the structure or number of cilia, which potentially lead to developmental disorder (Cortes et al, 2015). Mutations have been found in genes encoding IFT proteins and motor proteins that can cause a subclass of ciliopathies, such as short‐rib polydactyly syndrome (SRPS) (OMIM 613091) (Duran et al, 2017), which is characterized by a small rib cage, short limbs, and facial defects, typically cleft lip/palate (Turkmen et al, 2003). Genes responsible for SRPS include IFT172 , IFT140 , NEK1 , TCTN3 , DYNC2H1 , WDR60 , WDR34 , IFT80 , and WDR35 (Cavalcanti et al, 2011; Dagoneau et al, 2009; Halbritter et al, 2013; McInerney‐Leo et al, 2013; Mill et al, 2011; Perrault et al, 2012; Schmidts et al, 2013; Thiel et al, 2011; Thomas et al, 2012).…”

Section: Primary Cilia and Ofcsmentioning

confidence: 99%

Cellular and developmental basis of orofacial clefts

Garland

Sun

et al. 2020

Birth Defects Research

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During craniofacial development, defective growth and fusion of the upper lip and/or palate can cause orofacial clefts (OFCs), which are among the most common structural birth defects in humans. The developmental basis of OFCs includes morphogenesis of the upper lip, primary palate, secondary palate, and other orofacial structures, each consisting of diverse cell types originating from all three germ layers: the ectoderm, mesoderm, and endoderm. Cranial neural crest cells and orofacial epithelial cells are two major cell types that interact with various cell lineages and play key roles in orofacial development. The cellular basis of OFCs involves defective execution in any one or several of the following processes: neural crest induction, epithelial‐mesenchymal transition, migration, proliferation, differentiation, apoptosis, primary cilia formation and its signaling transduction, epithelial seam formation and disappearance, periderm formation and peeling, convergence and extrusion of palatal epithelial seam cells, cell adhesion, cytoskeleton dynamics, and extracellular matrix function. The latest cellular and developmental findings may provide a basis for better understanding of the underlying genetic, epigenetic, environmental, and molecular mechanisms of OFCs.

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“…More particularly, mutations in genes encoding components of IFT-A and IFT-B complexes often lead to skeletal dysplasia, including the short-rib thoracic dysplasia (SRTD; narrow thorax and chest, short ribs, short limbs, with or without polydactyly) or Sensenbrenner syndrome (SRTD signs with cranio-ectodermal dysplasia (craniosynostosis, dental abnormalities, spare hair)) (7). Nevertheless, other pathologies have been associated to IFT-A/IFT-B mutations, such as Bardet-Biedl syndrome, isolated retinal dystrophy and nephronophthisis-related disorders (8)(9)(10)(11)(12)(13)(14). Such phenotypic variability could be explained by the nature of the mutations; however, no clear genotype-phenotype correlations have been established.…”

Section: Introductionmentioning

confidence: 99%

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

Dupont

Humbert

Huber

et al. 2019

Human Molecular Genetics

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Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

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Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

Cited by 27 publications

References 43 publications

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Cellular and developmental basis of orofacial clefts

Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion

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