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Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification


The oral-facial-digital type I (OFD1) syndrome (OMIM 311200) is a human developmental disorder; affected individuals have craniofacial and digital abnormalities and, in 15% of cases, polycystic kidney1,2. The disease is inherited as an X-linked dominant male-lethal trait. Using a Cre-loxP system, we generated knockout animals lacking Ofd1 and reproduced the main features of the disease, albeit with increased severity, possibly owing to differences of X inactivation patterns between human and mouse. We found failure of left-right axis specification in mutant male embryos, and ultrastructural analysis showed a lack of cilia in the embryonic node. Formation of cilia was defective in cystic kidneys from heterozygous females, implicating ciliogenesis as a mechanism underlying cyst development. In addition, we found impaired patterning of the neural tube and altered expression of the 5′ Hoxa and Hoxd genes in the limb buds of mice lacking Ofd1, suggesting that Ofd1 could have a role beyond primary cilium organization and assembly.

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Figure 1: Ofd1Δ4–5/+ females show skeletal malformations at birth.
Figure 2: Cysts in the kidneys of P0 Ofd1Δ4–5/+ females lack primary cilia.
Figure 3: Laterality defects in Ofd1Δ4–5 male embryos.
Figure 4: Scanning electron microscopy of E7.5 embryos demonstrates absence of the nodal cilia in Ofd1Δ4–5 male mutants.
Figure 5: Ofd1Δ4–5 male mutants have abnormal specification of ventral neural tube cells.
Figure 6: Expression of markers for limb development in the Ofd1 knockout embryos.


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We thank C. Tabin, C.C. Hui, S. Mackem, D. Duboule and L. Selleri for providing in situ probes. We thank the Transgenic and Knockout Mouse Core Facility (TMCF) at Telethon Institute of Genetics and Medicine (TIGEM), P. Soriano for pGK-neo-bpA-lox2-PGK-DTA vector and A. Nagy for the pCX-NLS-Cre mouse line. We are also grateful to A. Baldini, C. Tabin, A. Woolf and J. Briscoe for helpful discussion and to S. Banfi, G. Diez-Roux and V. Marigo for critical reading of this manuscript. We wish to thank A. Ballabio for continuous and enthusiastic support and for fruitful discussion. This study was supported by grants from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale and Louis Pasteur University (N.M., P.D.); from the Italian Telethon Foundation and the Italian Ministry of Research (B.F.); and from the European Commission (grant QLRT-00791 to B.F.).

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Correspondence to Brunella Franco.

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Supplementary information

Supplementary Fig. 1

Targeted disruption of the mouse Ofd1 gene. (PDF 193 kb)

Supplementary Table 1

Oligonucleotide primers used for genomic PCR and RT-PCR as described in Methods. (PDF 58 kb)

Supplementary Note (PDF 82 kb)

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Ferrante, M., Zullo, A., Barra, A. et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 38, 112–117 (2006).

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