Cranio-lenticulo-sutural dysplasia associated with defects in collagen secretion

Article (PDF Available)inClinical Genetics 80(2):169-76 · September 2010with76 Reads
DOI: 10.1111/j.1399-0004.2010.01550.x · Source: PubMed
Boyadjiev SA, Kim S-D, Hata A, Haldeman-Englert C, Zackai EH, Naydenov C, Hamamoto S, Schekman RW, Kim J. Cranio-lenticulo-sutural dysplasia associated with defects in collagen secretion. Cranio-lenticulo-sutural dysplasia (CLSD) is a rare autosomal recessive syndrome manifesting with large and late-closing fontanels and calvarial hypomineralization, Y-shaped cataracts, skeletal defects, and hypertelorism and other facial dysmorphisms. The CLSD locus was mapped to chromosome 14q13-q21 and a homozygous SEC23A F382L missense mutation was identified in the original family. Skin fibroblasts from these patients exhibit features of a secretion defect with marked distension of the endoplasmic reticulum (ER), consistent with SEC23A function in protein export from the ER. We report an unrelated family where a male proband presented with clinical features of CLSD. A heterozygous missense M702V mutation in a highly conserved residue of SEC23A was inherited from the clinically unaffected father, but no maternal SEC23A mutation was identified. Cultured skin fibroblasts from this new patient showed a severe secretion defect of collagen and enlarged ER, confirming aberrant protein export from the ER. Milder collagen secretion defects and ER distention were present in paternal fibroblasts, indicating that an additional mutation(s) is present in the proband. Our data suggest that defective ER export is the cause of CLSD and genetic element(s) besides SEC23A may influence its presentation.


    • "Mutations in SEC23A result in accumulation of collagen in the ER (Boyadjiev et al. 2011 "
    [Show abstract] [Hide abstract] ABSTRACT: COPII vesicles mediate export of secretory cargo from the endoplasmic reticulum (ER). However, a standard COPII vesicle with a diameter of 60- 90 nm is too small to export collagens that are composed of rigid triple helices of up to 400 nm in length. How do cells pack and secrete such bulky molecules? This issue is fundamentally important, as collagens constitute approximately 25% of our dry body weight and are essential for almost all cell-cell interactions. Recently, a potential mechanism for the biogenesis of mega-transport carriers was identified, involving packing collagens and increasing the size of COPII coats. Packing is mediated by TANGO1, which binds procollagen VII in the lumen and interacts with the COPII proteins Sec23/Sec24 on the cytoplasmic side of the ER. Cullin3, an E3 ligase, and its specific adaptor protein, KLHL12, ubiquitinate Sec31, which could increase the size of COPII coats. Recruitment of these proteins and their specific interactors into COPII-mediated vesicle biogenesis may be all that is needed for the export of bulky collagens from the ER. Nonetheless, we present an alternative pathway in which TANGO1 and COPII cooperate to export collagens without generating a mega-transport carrier. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 31 is October 06, 2015. Please see for revised estimates.
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    • "To date two missense mutations located near the Sec31 binding site of the SEC23A folded protein were identified in patients. The F382L mutation was shown to hinder the ability of SEC23A to recruit the SEC13–SEC31 outer coat and to ultimately prevent vesicle budding (Fromme et al., 2007), whereas the M702V appears to activate SAR1B more efficiently than the wild type allele, resulting in premature dissociation of the COPII coat from ER membranes (Boyadjiev et al., 2011; Kim et al., 2012). Although other cargo molecules are packaged into COPII vesicles normally, procollagen accumulates in the ER of M702V mutant fibroblasts. "
    [Show abstract] [Hide abstract] ABSTRACT: Cellular life depends on protein transport and membrane traffic. In multicellular organisms, membrane traffic is required for extracellular matrix deposition, cell adhesion, growth factor release, and receptor signaling, which are collectively required to integrate the development and physiology of tissues and organs. Understanding the regulatory mechanisms that govern cargo and membrane flow presents a prime challenge in cell biology. Extracellular matrix (ECM) secretion remains poorly understood, although given its essential roles in the regulation of cell migration, differentiation, and survival, ECM secretion mechanisms are likely to be tightly controlled. Recent studies in vertebrate model systems, from fishes to mammals and in human patients, have revealed complex and diverse loss-of-function phenotypes associated with mutations in components of the secretory machinery. A broad spectrum of diseases from skeletal and cardiovascular to neurological deficits have been linked to ECM trafficking. These discoveries have directly challenged the prevailing view of secretion as an essential but monolithic process. Here, we will discuss the latest findings on mechanisms of ECM trafficking in vertebrates.
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    • "Plasma ApoC-III IEF was also abnormal and characterized by an increase in the monosialo-isoform and a decrease of the disialo-isoform [60]. SEC23A-CDG or craniolenticulosutural dysplasia is characterized by late-closing fontanels, sutural cataracts, facial dysmorphism, and skeletal defects caused by mutations in the SEC23A gene6162, which codes for an essential component of the COPII-coated vesicles that transport secretory proteins from the ER to the Golgi complex. The fibroblasts of these patients have gross dilatation of the ER due to accumulation of proteins and also cytoplasmic mislocalization of SEC31 an other essential component of the COPII coat [63]. "
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