Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

You are viewing this page in draft mode.

Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking


Cranio-lenticulo-sutural dysplasia (CLSD) is an autosomal recessive syndrome characterized by late-closing fontanels, sutural cataracts, facial dysmorphisms and skeletal defects mapped to chromosome 14q13–q21 (ref. 1). Here we show, using a positional cloning approach, that an F382L amino acid substitution in SEC23A segregates with this syndrome. SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. Electron microscopy and immunofluorescence show that there is gross dilatation of the endoplasmic reticulum in fibroblasts from individuals affected with CLSD. These cells also exhibit cytoplasmic mislocalization of SEC31. Cell-free vesicle budding assays show that the F382L substitution results in loss of SEC23A function. A phenotype reminiscent of CLSD is observed in zebrafish embryos injected with sec23a-blocking morpholinos. Our observations suggest that disrupted endoplasmic reticulum export of the secretory proteins required for normal morphogenesis accounts for CLSD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Craniofacial features of CLSD with depiction of the 1144T→C SEC23A mutation.
Figure 2: Immunofluorescence analysis.
Figure 3: Electron microscopy.
Figure 4: In vitro studies of F382L SEC23A.
Figure 5: Developmental expression of sec23a and loss-of-function phenotype in zebrafish.


  1. 1

    Boyadjiev, S.A. et al. A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13–q21. Hum. Genet. 113, 1–9 (2003).

    CAS  PubMed  Google Scholar 

  2. 2

    Duden, R. ER-to-Golgi transport: COP I and COP II function (review). Mol. Membr. Biol. 20, 197–207 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Schekman, R. & Orci, L. Coat proteins and vesicle budding. Science 271, 1526–1533 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Novick, P., Field, C. & Schekman, R. Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell 21, 205–215 (1980).

    CAS  Article  Google Scholar 

  5. 5

    Novick, P. & Schekman, R. Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 76, 1858–1862 (1979).

    CAS  Article  Google Scholar 

  6. 6

    Novick, P. & Schekman, R. Export of major cell surface proteins is blocked in yeast secretory mutants. J. Cell Biol. 96, 541–547 (1983).

    CAS  Article  Google Scholar 

  7. 7

    Barlowe, C. et al. COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum. Cell 77, 895–907 (1994).

    CAS  Article  Google Scholar 

  8. 8

    Antonny, B. & Schekman, R. ER export: public transportation by the COPII coach. Curr. Opin. Cell Biol. 13, 438–443 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Miller, E., Antonny, B., Hamamoto, S. & Schekman, R. Cargo selection into COPII vesicles is driven by the Sec24p subunit. EMBO J. 21, 6105–6113 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Miller, E.A. et al. Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles. Cell 114, 497–509 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Nakano, A., Brada, D. & Schekman, R. A membrane glycoprotein, Sec12p, required for protein transport from the endoplasmic reticulum to the Golgi apparatus in yeast. J. Cell Biol. 107, 851–863 (1988).

    CAS  Article  Google Scholar 

  12. 12

    Barlowe, C. & Schekman, R. SEC12 encodes a guanine-nucleotide-exchange factor essential for transport vesicle budding from the ER. Nature 365, 347–349 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Aridor, M., Weissman, J., Bannykh, S., Nuoffer, C. & Balch, W.E. Cargo selection by the COPII budding machinery during export from the ER. J. Cell Biol. 141, 61–70 (1998).

    CAS  Article  Google Scholar 

  14. 14

    Pagano, A. et al. Sec24 proteins and sorting at the endoplasmic reticulum. J. Biol. Chem. 274, 7833–7840 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Antonny, B., Madden, D., Hamamoto, S., Orci, L. & Schekman, R. Dynamics of the COPII coat with GTP and stable analogues. Nat. Cell Biol. 3, 531–537 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Bi, X., Corpina, R.A. & Goldberg, J. Structure of the Sec23/24-Sar1 pre-budding complex of the COPII vesicle coat. Nature 419, 271–277 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Roberts, B., Clucas, C. & Johnstone, I.L. Loss of SEC-23 in Caenorhabditis elegans causes defects in oogenesis, morphogenesis, and extracellular matrix secretion. Mol. Biol. Cell 14, 4414–4426 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Bottomley, M.J., Batten, M.R., Lumb, R.A. & Bulleid, N.J. Quality control in the endoplasmic reticulum: PDI mediates the ER retention of unassembled procollagen C-propeptides. Curr. Biol. 11, 1114–1118 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Nakamura, N. et al. Characterization of a cis-Golgi matrix protein, GM130. J. Cell Biol. 131, 1715–1726 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Kim, J., Hamamoto, S., Ravazzola, M., Orci, L. & Schekman, R. Uncoupled packaging of amyloid precursor protein and presenilin 1 into coat protein complex II vesicles. J. Biol. Chem. 280, 7758–7768 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Jones, B. et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat. Genet. 34, 29–31 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Tiller, G.E. et al. A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda. Am. J. Hum. Genet. 68, 1398–1407 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Zhang, B. et al. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat. Genet. 34, 220–225 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Fisher, L.W., Lindner, W., Young, M.F. & Termine, J.D. Synthetic peptide antisera: their production and use in the cloning of matrix proteins. Connect. Tissue. Res. 21, 43–48 (1989).

    CAS  Article  Google Scholar 

  25. 25

    Matsuoka, K. & Schekman, R. The use of liposomes to study COPII- and COPI-coated vesicle formation and membrane protein sorting. Methods 20, 417–428 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Wilson, R. et al. The translocation, folding, assembly and redox-dependent degradation of secretory and membrane proteins in semi-permeabilized mammalian cells. Biochem. J. 307, 679–687 (1995).

    CAS  Article  Google Scholar 

  27. 27

    Ben, J., Jabs, E.W. & Chong, S.S. Genomic, cDNA and embryonic expression analysis of zebrafish IRF6, the gene mutated in the human oral clefting disorders Van der Woude and popliteal pterygium syndromes. Gene Expr. Patterns 5, 629–638 (2005).

    CAS  Article  Google Scholar 

Download references


We thank all members of the family that participated in this project; C. Machamer and A. Hubbard for discussions and help with Immunofluorescence; J. Mendell for help with expression vectors, D. Murphy and C. Cooke for assistance with electron microscopy; A. Fischer for help with cell culture; J. Kim and B. Kleizen for assistance with in vitro assays; the Pole Facultaire de Microscopie Ultrastructurale (PFMU) at the University of Geneva Medical School for access to electron microscopy equipment and L. Liu for assistance with zebrafish imaging. This work was supported by grants from the National Institute of Dental and Craniofacial Research–US National Institutes of Health (DE16342 and DE00462 to S.A.B.) and the Swiss National Science Foundation (to L.O.); J.C.F. is supported by a fellowship from the Miller Institute for Basic Research; R.S. is supported by funds from the Howard Hughes Medical Institute and S.S.C. is supported by grants from the NUS (R-178-000-080-112 and R-178-000-104-112).

Author information




This study was initiated by S.A.B., who interpreted clinical and radiologic data, designed and performed experiments, and wrote the manuscript with contributions from J.C.F., R.S., L.O. and S.S.C.; W.E. performed the clinical assessment and provided fibroblast cell lines for these studies; S.A.B., D.J.H. and G.Z. performed the cloning experiments; R.S. and J.C.F. designed, performed and interpreted in vitro liposome-binding and vesicle-formation assays and contributed to immunofluorescence experiments. L.O., M.R. and S.H. performed electron microscopy and immunofluorescence analysis with contributions from C.N. and S.A.B.; L.O. critically interpreted microscopy data and suggested experiments; J.B. and S.S.C. performed the zebrafish expression analysis, the morpholino knockdown experiments and the analysis of the morphants.

Corresponding author

Correspondence to Simeon A Boyadjiev.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Craniofacial features of CLSD. (PDF 117 kb)

Supplementary Fig. 2

Cranial phenotype of CLSD. (PDF 383 kb)

Supplementary Fig. 3

Skeletal features of CLSD. (PDF 398 kb)

Supplementary Fig. 4

Effectiveness and specificity of translational inhibition of sec23a by antisense morpholinos P and Q. (PDF 79 kb)

Supplementary Table 1

Clnical and radiographic features of four sibs with CLSD as compared with FD, THS, HSS and CCD. (PDF 9 kb)

Supplementary Table 2

Primer and morpholino sequences. (PDF 8 kb)

Supplementary Note (PDF 12 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Boyadjiev, S., Fromme, J., Ben, J. et al. Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat Genet 38, 1192–1197 (2006).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing