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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 identified in a Jeune Syndrome patient.Family pedigree showing the relationship between JS1-1, JS 1-2, JS 1-3 and JS 1-4 (A; red arrow indicates the proband). Whole body (B), right (C) and left (D) upper limb and feet (E) radiographs from JS1-1. Note the short ribs, short long bones with bowed humeri and femora, “trident” appearance of the acetabular roofs and metaphyseal irregularity (B), short long bones with metaphyseal cupping and bowed humerus (C and D), and metaphyseal cupping and advanced tarsal bone ossification for age (E). A, acetabulum; F, femur; H, humerus; T, tarsus. Sequence chromatogram identifying the C>T homozygous mutation in JS1-1 (F; arrow), and heterozygous mutation in immediate family members.
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pgen-1003746-g006: An IFT140 mutation identified in a Jeune Syndrome patient.Family pedigree showing the relationship between JS1-1, JS 1-2, JS 1-3 and JS 1-4 (A; red arrow indicates the proband). Whole body (B), right (C) and left (D) upper limb and feet (E) radiographs from JS1-1. Note the short ribs, short long bones with bowed humeri and femora, “trident” appearance of the acetabular roofs and metaphyseal irregularity (B), short long bones with metaphyseal cupping and bowed humerus (C and D), and metaphyseal cupping and advanced tarsal bone ossification for age (E). A, acetabulum; F, femur; H, humerus; T, tarsus. Sequence chromatogram identifying the C>T homozygous mutation in JS1-1 (F; arrow), and heterozygous mutation in immediate family members.

Mentions: Patient JS 1-1 was the product of the first pregnancy to healthy, first-cousin Sudanese parents (Figure 6A). There was no extended family history of skeletal disorders. Short limbs (less than 5th centile for gestational age) and a short chest cage were noted on a third trimester ultrasound performed for growth assessment. No other abnormalities were observed at this time. The couple were counselled about a likely poor prognosis given the degree of thoracic hypoplasia. The child was delivered at 37 weeks of gestation with a birth head circumference of 37 cm (>98th centile) and birth length of 48 cm (50th centile). The baby was in poor condition and required high frequency ventilation with high peak pressures (32 mm Mercury) due to pulmonary hypoplasia and hypertension. On examination, the child had short square fingers and hands with five digits each, low nasal bridge, normal ears and palate, and hepatomegaly. A small muscular ventricular septal defect was found on echocardiography, and ultrasound of the enlarged liver showed normal hepatic texture. Normal liver and renal function was documented. The baby deteriorated, despite ventilation, and died aged 7 days. Post mortem radiography was obtained and revealed short long bones, with metaphyseal cupping, bowed femora and humeri, short ribs and thorax, trident appearance to the acetabular roofs, and advanced tarsal bone ossification (Figures 6B–E). These features are considered typical of classic Jeune asphyxiating thoracic dystrophy) syndrome.


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 identified in a Jeune Syndrome patient.Family pedigree showing the relationship between JS1-1, JS 1-2, JS 1-3 and JS 1-4 (A; red arrow indicates the proband). Whole body (B), right (C) and left (D) upper limb and feet (E) radiographs from JS1-1. Note the short ribs, short long bones with bowed humeri and femora, “trident” appearance of the acetabular roofs and metaphyseal irregularity (B), short long bones with metaphyseal cupping and bowed humerus (C and D), and metaphyseal cupping and advanced tarsal bone ossification for age (E). A, acetabulum; F, femur; H, humerus; T, tarsus. Sequence chromatogram identifying the C>T homozygous mutation in JS1-1 (F; arrow), and heterozygous mutation in immediate family members.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003746-g006: An IFT140 mutation identified in a Jeune Syndrome patient.Family pedigree showing the relationship between JS1-1, JS 1-2, JS 1-3 and JS 1-4 (A; red arrow indicates the proband). Whole body (B), right (C) and left (D) upper limb and feet (E) radiographs from JS1-1. Note the short ribs, short long bones with bowed humeri and femora, “trident” appearance of the acetabular roofs and metaphyseal irregularity (B), short long bones with metaphyseal cupping and bowed humerus (C and D), and metaphyseal cupping and advanced tarsal bone ossification for age (E). A, acetabulum; F, femur; H, humerus; T, tarsus. Sequence chromatogram identifying the C>T homozygous mutation in JS1-1 (F; arrow), and heterozygous mutation in immediate family members.
Mentions: Patient JS 1-1 was the product of the first pregnancy to healthy, first-cousin Sudanese parents (Figure 6A). There was no extended family history of skeletal disorders. Short limbs (less than 5th centile for gestational age) and a short chest cage were noted on a third trimester ultrasound performed for growth assessment. No other abnormalities were observed at this time. The couple were counselled about a likely poor prognosis given the degree of thoracic hypoplasia. The child was delivered at 37 weeks of gestation with a birth head circumference of 37 cm (>98th centile) and birth length of 48 cm (50th centile). The baby was in poor condition and required high frequency ventilation with high peak pressures (32 mm Mercury) due to pulmonary hypoplasia and hypertension. On examination, the child had short square fingers and hands with five digits each, low nasal bridge, normal ears and palate, and hepatomegaly. A small muscular ventricular septal defect was found on echocardiography, and ultrasound of the enlarged liver showed normal hepatic texture. Normal liver and renal function was documented. The baby deteriorated, despite ventilation, and died aged 7 days. Post mortem radiography was obtained and revealed short long bones, with metaphyseal cupping, bowed femora and humeri, short ribs and thorax, trident appearance to the acetabular roofs, and advanced tarsal bone ossification (Figures 6B–E). These features are considered typical of classic Jeune asphyxiating thoracic dystrophy) syndrome.

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