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Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes

Abstract

Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3–31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.

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Figure 1: Schematic representation of LRP2 mutations and corresponding megalin domains.
Figure 2: MRI abnormalities in individuals with DBS/FOAR.

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Acknowledgements

We thank the many families who supported this project. We thank D. Altshuler, D. Brown, M. Daly, J. Gusella, J. Ingelfinger, M. MacDonald and T.E. Willnow for discussions; L. Blakemore, J. Graham, Y. Lacassie, E. McPherson, A. Paterson, D. Powell, J. Tchinda Ndjuiken, D. Gleason, L. Mitova, K. O'Brien, and T. Manganaro for advice and assistance; L. Holmes for reporting the first family with FOAR and for encouraging this study from its inception; L. Javois and T. Hewitt for conceiving the US National Institute of Child Health and Human Development Birth Defects Initiative and encouraging and supporting this work. G.C.M.B. is a Wellcome Trust Senior Clinical Research Fellow. C.A.W. and R.S.H. are supported by US National Institute for Neurological Disorders and Stroke grant R37 NS35129. C.A.W. is an Investigator of the Howard Hughes Medical Institute. P.K.D., S.K., M.L., D.T.M., K.M.N., B.R.P. and M.K.R. are supported by R01 HD55150-01. K.M.N. is also supported by the 2006 American College of Surgeons' Resident Research Award.

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Contributions

S.K. designed and conducted experiments, interpreted data and prepared manuscript. K.M.N. designed and conducted experiments (urinary, immunostaining and RT-PCR), interpreted data and prepared manuscript. L.A.-G., G.C.M.B., E.B., N.C., D.D., K.D. and A.T. were clinical collaborators (recruiting DBS/FOAR kindreds and providing phenotypic information, patient samples and results of laboratory testing). G.C.M.B. prepared the manuscript as well. R.S.H. interpreted Affymetrix SNP array mapping and microsatellite marker genotyping and performed LOD score calculations. C.R. interpreted MRI scans. T.L. performed and analyzed MRI surface reconstructions of the brain. M.K.R. was the study coordinator, designed and implemented infrastructure, obtained institutional review board approval and consents, and assisted in conducting experiments. D.T.M. designed and interpreted (urinary) experiments, and designed and implemented infrastructure. M.L. designed and interpreted megalin expression studies. P.K.D., B.R.P. and C.A.W., who contributed equally to this work, conceived the project, designed infrastructure, supervised design of experiments and data interpretation, and prepared the manuscript.

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Correspondence to Barbara R Pober.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1–3 (PDF 6279 kb)

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Kantarci, S., Al-Gazali, L., Hill, R. et al. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 39, 957–959 (2007). https://doi.org/10.1038/ng2063

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