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Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome.

Miller KA, Ah-Cann CJ, Welfare MF, Tan TY, Pope K, Caruana G, Freckmann ML, Savarirayan R, Bertram JF, Dobbie MS, Bateman JF, Farlie PG - PLoS Genet. (2013)

Bottom Line: The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia.A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved.This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.

View Article: PubMed Central - PubMed

Affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

ABSTRACT
Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.

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Related in: MedlinePlus

An Ift140 mutation is responsible for the ciliopathic phenotype observed in cauli.Representative E13.5 wildtype (A) and mutant (B) embryos showing exencephaly (black arrowhead), open mouth (white arrowhead), polydactyly (asterisks) and caudal neural tube closure defects (arrow) in mutants. Chromatogram of cauli mutant showing the homozygous missense mutation (c.2564T>A) in the Intraflagellar Transport Protein 140 (Ift140) gene (C). IFT140 protein alignment showing the isoleucine to lysine substitution at position 855 of the protein in cauli and the corresponding amino acid across several species (D). Schematic of the IFT140 protein detailing protein domains, location of Ift140cauli/cauli mutation and reported human mutations (E). Mainzer-Saldino (black), Jeune asphyxiating thoracic dystrophy (red), +compound heterozygous, #homozygous ∧no second mutation identified. Black box represents mutation reported in this paper. Primary cilia from E10.5 Ift140+/+ (F) and Ift140cauli/cauli (G) limb buds show a severely altered cilia morphology in the mutant.
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pgen-1003746-g001: An Ift140 mutation is responsible for the ciliopathic phenotype observed in cauli.Representative E13.5 wildtype (A) and mutant (B) embryos showing exencephaly (black arrowhead), open mouth (white arrowhead), polydactyly (asterisks) and caudal neural tube closure defects (arrow) in mutants. Chromatogram of cauli mutant showing the homozygous missense mutation (c.2564T>A) in the Intraflagellar Transport Protein 140 (Ift140) gene (C). IFT140 protein alignment showing the isoleucine to lysine substitution at position 855 of the protein in cauli and the corresponding amino acid across several species (D). Schematic of the IFT140 protein detailing protein domains, location of Ift140cauli/cauli mutation and reported human mutations (E). Mainzer-Saldino (black), Jeune asphyxiating thoracic dystrophy (red), +compound heterozygous, #homozygous ∧no second mutation identified. Black box represents mutation reported in this paper. Primary cilia from E10.5 Ift140+/+ (F) and Ift140cauli/cauli (G) limb buds show a severely altered cilia morphology in the mutant.

Mentions: The cauli strain was identified via a comprehensive phenotype-driven ENU screen undertaken to identify novel genes involved in embryogenesis [17]. The vast majority of cauli homozygous embryos survive to approximately embryonic day (E) 13.5, however a small proportion has lived beyond this age (n = 10/130). No live embryos were obtained >E16.5. Fully penetrant phenotypes identified in cauli mutants include exencephaly (n = 130/130), anopthalmia (n = 130/130) and polydactyly of the hindlimbs (Figure 1B; n = 32/32 embryos analysed at >E12.5). Cauli mutants were developmentally delayed compared to wildtype littermates and additional phenotypes observed in these mice include oligodactyly of the forelimbs, gaping mouth, omphaloceole, oedema, curly tail and caudal neural tube closure defects (Figures 1A and B).


Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome.

Miller KA, Ah-Cann CJ, Welfare MF, Tan TY, Pope K, Caruana G, Freckmann ML, Savarirayan R, Bertram JF, Dobbie MS, Bateman JF, Farlie PG - PLoS Genet. (2013)

An Ift140 mutation is responsible for the ciliopathic phenotype observed in cauli.Representative E13.5 wildtype (A) and mutant (B) embryos showing exencephaly (black arrowhead), open mouth (white arrowhead), polydactyly (asterisks) and caudal neural tube closure defects (arrow) in mutants. Chromatogram of cauli mutant showing the homozygous missense mutation (c.2564T>A) in the Intraflagellar Transport Protein 140 (Ift140) gene (C). IFT140 protein alignment showing the isoleucine to lysine substitution at position 855 of the protein in cauli and the corresponding amino acid across several species (D). Schematic of the IFT140 protein detailing protein domains, location of Ift140cauli/cauli mutation and reported human mutations (E). Mainzer-Saldino (black), Jeune asphyxiating thoracic dystrophy (red), +compound heterozygous, #homozygous ∧no second mutation identified. Black box represents mutation reported in this paper. Primary cilia from E10.5 Ift140+/+ (F) and Ift140cauli/cauli (G) limb buds show a severely altered cilia morphology in the mutant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757063&req=5

pgen-1003746-g001: An Ift140 mutation is responsible for the ciliopathic phenotype observed in cauli.Representative E13.5 wildtype (A) and mutant (B) embryos showing exencephaly (black arrowhead), open mouth (white arrowhead), polydactyly (asterisks) and caudal neural tube closure defects (arrow) in mutants. Chromatogram of cauli mutant showing the homozygous missense mutation (c.2564T>A) in the Intraflagellar Transport Protein 140 (Ift140) gene (C). IFT140 protein alignment showing the isoleucine to lysine substitution at position 855 of the protein in cauli and the corresponding amino acid across several species (D). Schematic of the IFT140 protein detailing protein domains, location of Ift140cauli/cauli mutation and reported human mutations (E). Mainzer-Saldino (black), Jeune asphyxiating thoracic dystrophy (red), +compound heterozygous, #homozygous ∧no second mutation identified. Black box represents mutation reported in this paper. Primary cilia from E10.5 Ift140+/+ (F) and Ift140cauli/cauli (G) limb buds show a severely altered cilia morphology in the mutant.
Mentions: The cauli strain was identified via a comprehensive phenotype-driven ENU screen undertaken to identify novel genes involved in embryogenesis [17]. The vast majority of cauli homozygous embryos survive to approximately embryonic day (E) 13.5, however a small proportion has lived beyond this age (n = 10/130). No live embryos were obtained >E16.5. Fully penetrant phenotypes identified in cauli mutants include exencephaly (n = 130/130), anopthalmia (n = 130/130) and polydactyly of the hindlimbs (Figure 1B; n = 32/32 embryos analysed at >E12.5). Cauli mutants were developmentally delayed compared to wildtype littermates and additional phenotypes observed in these mice include oligodactyly of the forelimbs, gaping mouth, omphaloceole, oedema, curly tail and caudal neural tube closure defects (Figures 1A and B).

Bottom Line: The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia.A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved.This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.

View Article: PubMed Central - PubMed

Affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia.

ABSTRACT
Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.

Show MeSH
Related in: MedlinePlus