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

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_Am. J. Pathol._ 162, 547–555 (2003). Article  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * Sibel Kantarci, Lihadh Al-Gazali and R Sean Hill: These authors contributed equally to this work. AUTHORS AND

AFFILIATIONS * Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Simches Research Building, 185 Cambridge St., Boston, 02114, Massachusetts, USA Sibel Kantarci, Maria

Loscertales, David T MacLaughlin, Kristin M Noonan, Meaghan K Russell, Patricia K Donahoe & Barbara R Pober * Department of Pediatrics, Faculty of Medicine and Health Sciences, United

Arab Emirates University, Al Ain, United Arab Emirates Lihadh Al-Gazali * Department of Neurology, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA R Sean Hill & 

Christopher A Walsh * Unit of Medical Genetics, University of Manchester, St Mary's Hospital, Manchester, M13 0JH, UK Dian Donnai & Graeme C M Black * Hôpital Purpan, 31059 Toulouse

cedex 9, France and CHU Pellegrin, Bordeaux, France Eric Bieth & Nicolas Chassaing * Service de Génétique Médicale, Hôpital Pelligrin, CHU de Bordeaux, Bordeaux, France Nicolas

Chassaing & Didier Lacombe * Center for Human Genetics, University of Leuven, Leuven, B-3000, Belgium Koen Devriendt * Departments of Pediatrics and Genetic Medicine, Weill Cornell

Medical College in Qatar, and Hamad Medical City, Doha, Qatar Ahmad Teebi * Departments of Surgery, Pediatrics, Radiology, and Neurology, Harvard Medical School, Boston, 02115,

Massachusetts, USA Sibel Kantarci, R Sean Hill, Maria Loscertales, Caroline Robson, Tianming Liu, David T MacLaughlin, Kristin M Noonan, Christopher A Walsh, Patricia K Donahoe & Barbara

R Pober * Children's Hospital, Boston, 02115, Massachusetts, USA Caroline Robson, Christopher A Walsh & Barbara R Pober * Center for Bioinformatics, Harvard Center for

Neurodegeneration and Repair, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA Tianming Liu * Pediatrics, MassGeneral Hospital for Children, Simches Research Building,

185 Cambridge St., Boston, 02114, Massachusetts, USA Barbara R Pober Authors * Sibel Kantarci View author publications You can also search for this author inPubMed Google Scholar * Lihadh

Al-Gazali View author publications You can also search for this author inPubMed Google Scholar * R Sean Hill View author publications You can also search for this author inPubMed Google

Scholar * Dian Donnai View author publications You can also search for this author inPubMed Google Scholar * Graeme C M Black View author publications You can also search for this author

inPubMed Google Scholar * Eric Bieth View author publications You can also search for this author inPubMed Google Scholar * Nicolas Chassaing View author publications You can also search for

this author inPubMed Google Scholar * Didier Lacombe View author publications You can also search for this author inPubMed Google Scholar * Koen Devriendt View author publications You can

also search for this author inPubMed Google Scholar * Ahmad Teebi View author publications You can also search for this author inPubMed Google Scholar * Maria Loscertales View author

publications You can also search for this author inPubMed Google Scholar * Caroline Robson View author publications You can also search for this author inPubMed Google Scholar * Tianming Liu

View author publications You can also search for this author inPubMed Google Scholar * David T MacLaughlin View author publications You can also search for this author inPubMed Google

Scholar * Kristin M Noonan View author publications You can also search for this author inPubMed Google Scholar * Meaghan K Russell View author publications You can also search for this

author inPubMed Google Scholar * Christopher A Walsh View author publications You can also search for this author inPubMed Google Scholar * Patricia K Donahoe View author publications You

can also search for this author inPubMed Google Scholar * Barbara R Pober View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Barbara R Pober. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Methods, Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1–3 (PDF 6279 kb)

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 13 February 2007

* Accepted: 24 May 2007 * Published: 15 July 2007 * Issue Date: August 2007 * DOI: https://doi.org/10.1038/ng2063 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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