A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking

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• 作者：Adila Al-Kindi (1)
  Praseetha Kizhakkedath (2)
  Huifang Xu (3)
  Anne John (2)
  Abeer Al Sayegh (1)
  Anuradha Ganesh (4)
  Maha Al-Awadi (1)
  Lamya Al-Anbouri (1)
  Lihadh Al-Gazali (5)
  Birgit Leitinger (3)
  Bassam R Ali (2)
  
  1. Department of Genetics ; Sultan Qaboos University Hospital ; Sultan Qaboos University ; Al koudh ; 123 ; Muscat Sultanate of Oman
  2. Department of Pathology ; College of Medicine and Heath Sciences ; United Arab Emirates University ; P.O. Box 17666 ; Al Ain ; United Arab Emirates
  3. National Heart and Lung Institute ; Imperial College London ; London ; SW7 2AZ ; United Kingdom
  4. Pediatric Ophthalmology ; Sultan Qaboos University Hospital ; Sultan Qaboos University ; Alkoudh ; 123 ; Muscat ; Sultanate of Oman
  5. Department of Paediatrics ; College of Medicine and Heath Sciences ; United Arab Emirates University ; Al Ain ; United Arab Emirates
  
• 关键词：DDR2 ; Spondylo ; meta ; epiphyseal dysplasia ; Trafficking defect ; SMED ; SL ; ERAD ; Optic atrophy
• 刊名：BMC Medical Genetics
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：15
• 期：1
• 全文大小：839 KB
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  47. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2350/15/42/prepub
  
• 刊物主题：Human Genetics; Genetics and Population Dynamics;
• 出版者：BioMed Central
• ISSN：1471-2350

文摘

Background The rare autosomal genetic disorder, Spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL), is reported to be caused by missense or splice site mutations in the human discoidin domain receptor 2 (DDR2) gene. Previously our group has established that trafficking defects and loss of ligand binding are the underlying cellular mechanisms of several SMED-SL causing mutations. Here we report the clinical characteristics of two siblings of consanguineous marriage with suspected SMED-SL and identification of a novel disease-causing mutation in the DDR2 gene. Methods Clinical evaluation and radiography were performed to evaluate the patients. All the coding exons and splice sites of the DDR2 gene were sequenced by Sanger sequencing. Subcellular localization of the mutated DDR2 protein was determined by confocal microscopy, deglycosylation assay and Western blotting. DDR2 activity was measured by collagen activation and Western analysis. Results In addition to the typical features of SMED-SL, one of the patients has an eye phenotype including visual impairment due to optic atrophy. DNA sequencing revealed a novel homozygous dinucleotide deletion mutation (c.2468_2469delCT) on exon 18 of the DDR2 gene in both patients. The mutation resulted in a frameshift leading to an amino acid change at position S823 and a predicted premature termination of translation (p.S823Cfs*2). Subcellular localization of the mutant protein was analyzed in mammalian cell lines, and it was found to be largely retained in the endoplasmic reticulum (ER), which was further supported by its N-glycosylation profile. In keeping with its cellular mis-localization, the mutant protein was found to be deficient in collagen-induced receptor activation, suggesting protein trafficking defects as the major cellular mechanism underlying the loss of DDR2 function in our patients. Conclusions Our results indicate that the novel mutation results in defective trafficking of the DDR2 protein leading to loss of function and disease. This confirms our previous findings that DDR2 missense mutations occurring at the kinase domain result in retention of the mutant protein in the ER.