Abstract
Mulibrey nanism (for muscle-liver-brain-eye nanism, MUL; MIM 253250) is an autosomal recessive disorder that involves several tissues of mesodermal origin, implying a defect in a highly pleiotropic gene1. Characteristic features include severe growth failure of prenatal onset and constrictive pericardium with consequent hepatomegaly1,2,3. In addition, muscle hypotonia, J-shaped sella turcica, yellowish dots in the ocular fundi, typical dysmorphic features and hypoplasia of various endocrine glands causing hormonal deficiency are common1,2,3. About 4% of MUL patients develop Wilms′ tumour2,4,5. MUL is enriched in the Finnish population, but is rare elsewhere1,2,3. We previously assigned MUL to chromosome 17q22–q23 and constructed a physical contig over the critical MUL region6,7. The region has now been further refined by haplotype analysis and new positional candidate genes have been localized. We identified a gene with four independent MUL-associated mutations that all cause a frameshift and predict a truncated protein. MUL is ubiquitously expressed and encodes a new member of the RING-B-box-Coiled-coil (RBCC) family of zinc-finger proteins8,9,10, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
39,95 €
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Perheentupa, J., Autio, S., Leisti, S., Raitta, C. & Tuuteri, L. Mulibrey-nanism, an autosomal recessive syndrome with pericardial constriction. Lancet 2, 351–355 (1973).
Lipsanen-Nyman, M. Mulibrey-nanismi Thesis, Univ. Helsinki (1986).
Lapunzina, P., Rodriguez, J.I., de Matteo, E., Gracia, R. & Moreno, F. Mulibrey nanism: three additional patients and a review of 39 patients. Am. J. Med. Genet. 55, 349–355 (1995).
Similä, S., Timonen, M. & Heikkinen, E. A case of mulibrey nanism with associated Wilms' tumor. Clin. Genet. 17, 29–30 (1980).
Seemanová, E. & Bartch, O. Mulibrey nanism and Wilms' tumor. Am. J. Med. Genet. 85, 76–78 (1999).
Avela, K. et al. Assignment of the mulibrey nanism gene to 17q by linkage and linkage disequilibrium analysis. Am. J. Hum. Genet. 60, 896–902 (1997).
Paavola, P. et al. High-resolution physical and genetic mapping of the critical region for meckel syndrome and mulibrey nanism on chromosome 17q22–q23. Genome Res. 9, 267–276 (1999).
Reddy, B.A., Etkin, L.D. & Freemont, P.S. A novel zinc finger coiled-coil domain in a family of nuclear proteins. Trends Biochem. Sci. 17, 344–345 (1992).
Saurin, A.J., Borden, K.L.B., Boddy, M.N. & Freemont, P.S. Does this have a familiar RING? Trends Biochem. Sci. 21, 208–214 (1996).
Slack, F. J. & Ruvkun, G. A novel repeat domain that is often associated with RING finger and B-box motifs. Trends Biochem. Sci. 23, 474–475 (1998).
Nagase, T. et al. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5, 355–364 (1998).
Nagai, Y. et al. Identification of a novel nuclear speckle-type protein, SPOP. FEBS Lett. 418, 23–26 (1997).
Dow, M.R. & Mains, P.E. Genetic and molecular characterization of the caenorhabditis elegans gene, mel-26, a postmeiotic negative regulator of mei-1, a meiotic-specific spindle component. Genetics 150, 119–128 (1998).
Nakai, K. & Horton, P. PSORT: a program for detecting the sorting signals of proteins and predicting their subcellular localization. Trends Biochem. Sci. 24, 34–35 (1999).
Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).
Peltonen, L., Jalanko, A. & Varilo, T. Molecular genetics of the Finnish disease heritage. Hum. Mol. Genet. 8, 1913–1923 (1999).
Ranta, S. et al. The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genet. 23, 233–236 (1999).
Cooper, D.N. & Krawczak, M. Mechanisms of insertional mutagenesis in human genes causing genetic disease. Hum. Genet. 87, 409–415 (1991).
Borden, K.L. et al. In vivo and in vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML. Proc. Natl Acad. Sci. USA 93, 1601–1606 (1996).
Wu, L.C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14, 430–440 (1996).
Borden, K.L. et al. Characterisation of a novel cysteine/histidine-rich metal binding domain from Xenopus nuclear factor XNF7. FEBS Lett. 335, 255–260 (1993).
Le Douarin, B., You, J., Nielsen, A.L., Chambon, P. & Losson, R. TIF1α: a possible link between KRAB zinc finger proteins and nuclear receptors. J. Steroid Biochem. Mol. Biol. 65, 43–50 (1998).
Chang, C.-J., Chen, Y.-L. & Lee, S.-C. Coactivator TIF1β interacts with transcription factor C/EBPβ and glucocorticoid receptor to induce α1-acid glycoprotein gene expression. Mol. Cell. Biol. 18, 5880–5887 (1998).
de The H. et al. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).
Takahashi, M., Inaguma, Y., Hiai, H. & Hirose, F. Developmentally regulated expression of a human “finger”-containing gene encoded by the 5′ half of the ret transforming gene. Mol. Cell. Biol. 8, 1853–1856 (1988).
Le Douarin, B. et al. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J. 14, 2020–2033 (1995).
Rahman, N. et al. Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12–21. Nature Genet. 13, 461–463 (1996).
The French FMF consortium. A candidate gene for familial Mediterranean fever. Nature Genet. 17, 25–31 (1997).
Quaderi, N.A. et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nature Genet. 17, 285–291 (1997).
Cainarca, S., Messali, S., Ballabio, A. & Meroni, G. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum. Mol. Genet. 8, 1387–1396 (1999).
Culbertson, M.R. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 15, 74–80 (1999).
Acknowledgements
We thank the families for cooperation; S. Lindh for helping to collect materials; P. Sistonen of the Finnish Red Cross Blood Transfusion Service for providing DNA from Finnish control individuals; and M. Gardiner for critical reading of the manuscript. This study was supported by the Academy of Finland, the Ulla Hjelt Fund for the Foundation of Pediatric Research in Finland, the Maud Kuistila Foundation and the Finnish Medical Society Duodecim, and by National Cancer Institute grant P30 CA16058.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Avela, K., Lipsanen-Nyman, M., Idänheimo, N. et al. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Nat Genet 25, 298–301 (2000). https://doi.org/10.1038/77053
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1038/77053
