Collagen XVIII Mutation in Knobloch Syndrome With Acute Lymphoblastic Leukemia

Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2010; 152A(11):2875-9. DOI: 10.1002/ajmg.a.33621
Source: PubMed


Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and vitreoretinal degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy.

Download full-text


Available from: Vinit B Mahajan,
  • Source
    • "Genes responsible for myopia in association with other genetic syndromes have been identified: COL2A1 and COL11A1 for Stickler syndromes type 1 and 2 respectively (Annunen et al., 1999; Heikkinen et al., 1997), lysyl-protocollagen hydroxylase for type VI Ehlers-Danlos syndrome (Mahajan et al., 2010), COL18/A1 for Knobloch syndrome (Kainulainen et al., 1994) and fibrillin for Fig. 3. Age-related changes in decorin/DS-PG-II in human sclera and articular cartilage. A) Decorin was extracted from human sclera from ages 2 months to 94 years (n ¼ 15), separated from other sulfated proteoglycans and quantified as micrograms of glycosaminoglycan per gram wet weight. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myopia is a common ocular condition, characterized by excessive elongation of the ocular globe. The prevalence of myopia continues to increase, particularly among highly educated groups, now exceeding 80% in some groups. In parallel with the increased prevalence of myopia, are increases in associated blinding ocular conditions including glaucoma, retinal detachment and macular degeneration, making myopia a significant global health concern. The elongation of the eye is closely related to the biomechanical properties of the sclera, which in turn are largely dependent on the composition of the scleral extracellular matrix. Therefore an understanding of the cellular and extracellular events involved in the regulation of scleral growth and remodeling during childhood and young adulthood will provide future avenues for the treatment of myopia and its associated ocular complications. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 04/2015; 133. DOI:10.1016/j.exer.2014.07.015 · 2.71 Impact Factor
  • Source
    • "The phenotype includes retinal detachment , nystagmus and congenital meningocele . While vitreoretinal degeneration is the more common phenotype seen in KS patients , our patient showed chorioretinal degeneration , a rather uncommon phenotype , which has been previously reported by Mahajan et al . 2010 [ 18 ] . Two of the family members of the patient had extreme myopia , which is a phenotype frequently observed in KS patients . However , this did not segregate with the COL18A1 mutation in the family . The spectrum of ophthalmologic findings in KS was docu - mented in a recent report by Khan et al [ 34 ] in eight patients . Six of the"
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients’ DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.
    PLoS ONE 11/2014; 9(11). DOI:10.1371/journal.pone.0112747 · 3.23 Impact Factor
  • Source
    • "Our current finding of Nid1 and Lamc1 mutations in ADDWOC patients indicates that the ECM is required for the normal structural integrity of the developing posterior fossa. Interestingly, mutations in the COL18A1 gene (encoding type XVIII collagen), another member of the Nid1 interactome, cause Knobloch syndrome, which is characterized by occipital cephaloceles [Mahajan et al., 2010; Sertie et al., 2000], and type XVIII collagen and Nid1 interact physically to support the BM even in species as distant from human as Caenorhabditis elegans [Ackley et al., 2003]. Mice harboring missense or stop mutations in Nid1 and Lamc1 have not been described, but mice with deletions in these genes do display BM abnormalities and neurological deficits. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We performed whole-exome sequencing of a family with autosomal dominant Dandy-Walker malformation and occipital cephaloceles and detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the ECM in the pathogenesis of Dandy-Walker spectrum disorders. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; 34(8). DOI:10.1002/humu.22351 · 5.14 Impact Factor
Show more