Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

[1]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[2]  T. Komori,et al.  Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. , 2005, Genes & development.

[3]  M. le Merrer,et al.  Acrofacial dysostoses. , 1989, American journal of medical genetics.

[4]  A. Kolokythas,et al.  Temporomandibular joint replacement for ankylosis correction in Nager syndrome: case report and review of the literature. , 2012, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[5]  P. A. Friedman,et al.  Nager acrofacial dysostosis: male-to-male transmission in 2 families. , 1991, American journal of medical genetics.

[6]  E. Haan,et al.  Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene , 2012, Clinical genetics.

[7]  P. Doevendans,et al.  Developmental expression of the murine spliceosome‐associated protein mSAP49 , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  R. Reed,et al.  The prespliceosome components SAP 49 and SAP 145 interact in a complex implicated in tethering U2 snRNP to the branch site. , 1994, Genes & development.

[9]  M. Blaustein,et al.  Signals, pathways and splicing regulation. , 2007, The international journal of biochemistry & cell biology.

[10]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[11]  J. Opitz,et al.  Differential diagnosis of Nager acrofacial dysostosis syndrome: report of four patients with Nager syndrome and discussion of other related syndromes. , 1983, American journal of medical genetics.

[12]  B. Mogilner,et al.  Autosomal recessive inheritance of Nager acrofacial dysostosis. , 1988, Journal of medical genetics.

[13]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[14]  B. Robert Bone morphogenetic protein signaling in limb outgrowth and patterning , 2007, Development, growth & differentiation.

[15]  Marvin Miller,et al.  Postaxial acrofacial dysostosis syndrome. , 1979, The Journal of pediatrics.

[16]  D. Horn,et al.  Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. , 2012, American journal of human genetics.

[17]  C. Rivolta,et al.  A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. , 2011, American journal of human genetics.

[18]  Sandya Liyanarachchi,et al.  Mutations in U4atac snRNA, a Component of the Minor Spliceosome, in the Developmental Disorder MOPD I , 2011, Science.

[19]  M. Shionyu,et al.  Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation* , 2007, Journal of Biological Chemistry.

[20]  M. McDonald,et al.  Nager acrofacial dysostosis. , 1993, Journal of medical genetics.

[21]  T. Waldman,et al.  Interaction of the BMPR-IA tumor suppressor with a developmentally relevant splicing factor. , 2004, Biochemical and biophysical research communications.

[22]  J. Vilardell,et al.  Regulated pre-mRNA splicing: the ghostwriter of the eukaryotic genome. , 2012, Biochimica et biophysica acta.

[23]  C. Larsson,et al.  Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. , 2009, American journal of human genetics.

[24]  S. Kennedy,et al.  Newly recognized autosomal recessive acrofacial dysostosis syndrome resembling Nager syndrome , 2004, American journal of medical genetics. Part A.

[25]  B. Hall Nager acrofacial dysostosis: autosomal dominant inheritance in mild to moderately affected mother and lethally affected phocomelic son. , 1989, American journal of medical genetics.

[26]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[27]  D. Waggoner,et al.  Deletion of 1q in a patient with acrofacial dysostosis. , 1999, American journal of medical genetics.

[28]  J. Shendure,et al.  Exome sequencing as a tool for Mendelian disease gene discovery , 2011, Nature Reviews Genetics.

[29]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[30]  D. Mackey,et al.  Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). , 2001, Human molecular genetics.

[31]  J. Opitz,et al.  Nager “syndrome” versus “anomaly” and its nosology with the postaxial acrofacial dysostosis syndrome of Genée and Wiedemann , 1987 .

[32]  D. Hunt,et al.  A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). , 2001, Molecular cell.

[33]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[34]  F. Nager,et al.  Das Gehörorgan Bei Den Angeborenen Kopfmissbildungen , 1948 .