TY - JOUR
T1 - OFD1 Is Mutated in X-Linked Joubert Syndrome and Interacts with LCA5-Encoded Lebercilin
AU - Coene, Karlien L.M.
AU - Roepman, Ronald
AU - Doherty, Dan
AU - Afroze, Bushra
AU - Kroes, Hester Y.
AU - Letteboer, Stef J.F.
AU - Ngu, Lock H.
AU - Budny, Bartlomiej
AU - van Wijk, Erwin
AU - Gorden, Nicholas T.
AU - Azhimi, Malika
AU - Thauvin-Robinet, Christel
AU - Veltman, Joris A.
AU - Boink, Mireille
AU - Kleefstra, Tjitske
AU - Cremers, Frans P.M.
AU - van Bokhoven, Hans
AU - de Brouwer, Arjan P.M.
N1 - Funding Information:
We thank the families for their valuable contribution to this research. We are also indebted to Lydie Burglen (Service de Génétique et Embryologie Médicales CHU Hôpital d'Enfants Armand-Trousseau, Paris, France) for providing the cell lines of the female patient with the p.I271fs mutation and to Saskia van der Velde and Christel Beumer (Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands) for expert technical assistance with cell culturing. We thank Ian Glass and Melissa Parisi (Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, USA) for providing clinical details on subject UW87. We also thank Uwe Wolfrum (Johannes-Gutenberg Universität, Mainz, Germany) for providing the hTERT-RPE1 cell line and the α-centrin monoclonal antibody, E. Nigg (Max-Planck Institut für Biochemie, Martinsried, Germany) for providing α-OFD1 serum, Carsten Janke (CNRS Centre de Recherches en Biochimie Macromoléculaire, Montpellier, France) for providing the GT335 monoclonal antibody, and Brunella Franco (TIGEM Telethon Institute of Genetics and Medicine, Naples, Italy) for providing the full-length OFD1 clone. This work was supported by The Netherlands Organization for Scientific Research (NWO Toptalent-021.001.014 to K.L.M.C. and NWO Vidi-91786396 to R.R.), the Foundation for Retinal Research (R.R. and F.P.M.C.), the Foundation Fighting Blindness (BR-CMM-0808-0451-RAD to R.R.), the United States National Institutes of Health (NCRR 5KL2RR025015 to D.D.), and the March of Dimes Endowment for Healthier Babies (to D.D.).
PY - 2009/10/9
Y1 - 2009/10/9
N2 - We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.
AB - We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.
UR - https://www.scopus.com/pages/publications/70350494065
U2 - 10.1016/j.ajhg.2009.09.002
DO - 10.1016/j.ajhg.2009.09.002
M3 - Article
C2 - 19800048
AN - SCOPUS:70350494065
SN - 0002-9297
VL - 85
SP - 465
EP - 481
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -