Cranio-lenticulo-sutural-dysplasia (CLSD) is a congenital autosomal recessive disease characterized by facial dysmorphisms, skeletal defects, late-closing fontanels, and cataracts. Missense mutations (F382L and M702V) in SEC23A have been linked to CLSD. SEC23A is an essential component of the COPII-coated vesicles that transport secretory and membrane proteins from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment (ERGIC) or cis-Golgi. COPII proteins (SAR1, SEC13/31, and SEC23/24) deform the ER membrane into a small transport vesicle. During this vesicle assembly, the COPII proteins load cargo molecules into a budding vesicle. Defects in COPII proteins cause inefficient export of cargo proteins from the ER, resulting in gross dilation of the ER in yeast. Fibroblasts derived from CLSD patients also show distention of the ER, clearly demonstrating an ER export defect. Surprisingly, however, most cargo molecules traffic normally in M702V fibroblasts. This result suggests that M702V SEC23A blocks ER export in a cargo specific manner and that a trafficking defect of a specific set of cargo proteins is the underlying cause of this disease. Remarkably, we recently observed that the mitogen-activated protein kinase (MAPK) signaling is down regulated in the M702V fibroblasts. This is interesting because the MAPK pathway relays signals from receptor tyrosine kinases (RTKs) to downstream effectors. Constitutive hyperactivation of a RTK, fibroblast growth factor receptor (FGFR), accounts for most cases of familial craniosynostosis (CS), the premature fusion of the cranial sutures. Lessening this aberrant MAPK signaling by an inhibitor of this pathway was sufficient to rescue CS phenotypes in mice. Because excessive FGFR-MAPK signaling leads to premature closure of craniofacial sutures, deficient MAPK signaling in the M702V cells likely contributes to delayed closure of craniofacial sutures in CLSD. Thus, M702V SEC23A may specifically inhibit trafficking of RTKs. A recent study has revealed that activation of extracellular signal-regulated kinase 2 (a MAPK) by epidermal growth factor enhances formation of ER exit sites, indicating an efficient assembly of COPII vesicles. Considering the notion that hyperactivation of the MAPK signaling contributes to CS, the premature fusion of cranial sutures may be mediated by an increased efficiency of ER export. Thus, understanding the interplay between the RTK signaling and the COPII vesicle assembly via the MAPK pathway can provide a fundamentally critical insight into CLSD, CS, and other related diseases. We hypothesize that the MAPK pathway connects signaling from RTKs to the ER export machinery. This model predicts that in CLSD, deficiency of SEC23A causes inefficient trafficking of RTKs, resulting in reduced MAPK signaling and that in CS, enhanced FGFR-MAPK signaling causes excessively increased ER export. To test these predictions, we will test if a SEC23A deficit blocks ER export of RTKs and influences the MAPK signaling (CLSD case) and we will test whether the overactive FGFR-MAPK signaling causes an excessive assembly of COPII vesicles (CS case).

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Cranio-lenticulo-sutural dysplasia (CLSD) is caused by mutations (F382L or M702V) in SEC23A, a component of COPII machinery that is critical for protein export from the endoplasmic reticulum (ER). We recently discovered that the ER export defect in M702V fibroblasts cells is cargo specific and that the MAPK signaling pathway is subdued possibly because of a trafficking defect of receptor tyrosine kinases including FGFR. By using Sec23a-deficient human and murine cell lines, we will characterize the interplay between ER export machinery and the MAPK signaling pathway in the context of craniofacial development, which will allow us to decipher the significance of protein transport on craniofacial development and to design new strategies for treatment of craniofacial defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Scholnick, Steven
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University of California Davis
Schools of Medicine
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Justice, Cristina M; Kim, Jinoh; Kim, Sun-Don et al. (2017) A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. Am J Med Genet A 173:2893-2897
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