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Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism

Nature Genetics volume 25, pages 298–301 (2000)Cite this article

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.

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Figure 1: Physical map of the critical MUL region.
Figure 2: Schematic diagrams of MUL proteins.
Figure 3: MUL is ubiquitously expressed.
Figure 4: Sequencing chromatograms of four MUL patients and controls representing the homozygous c.493-2A>G (Finmajor) mutation (a); the heterozygous c.2212delG (Finminor) mutation (b); the homozygous c.838delACTTT (Czech) mutation (c); and the homozygous c.134insA (American) mutation (d).

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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.

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Authors and Affiliations

  1. Folkhälsan Institute of Genetics, Helsinki, Finland

    Kristiina Avela, Niina Idänheimo, Albert de la Chapelle & Anna-Elina Lehesjoki

  2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland

    Kristiina Avela, Niina Idänheimo & Anna-Elina Lehesjoki

  3. The Hospital for Children and Adolescents, University of Helsinki, Finland

    Marita Lipsanen-Nyman & Jaakko Perheentupa

  4. Institute of Biology and Medical Genetics, 2nd Medical School, Charles University, Prague-Motol, Czech Republic

    Eva Seemanová

  5. University of Connecticut School of Medicine, Farmington, Connecticut, USA

    Sally Rosengren

  6. Haartman Institute & Biocentrum Helsinki, University of Helsinki, Finland

    Tomi P. Mäkelä

  7. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

    Albert de la Chapelle

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  1. Kristiina Avela
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Correspondence to Kristiina Avela.

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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

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