Clinical, radiographic and molecular characterization of two unrelated families with multicentric osteolysis, nodulosis, and arthropathy

BMC Musculoskeletal Disorders

Research

Go Hun Seo¹  Petra Loid²  Outi Mäkitie³  Tayyaba Ishaq⁴  Sadaf Naz⁴  Hafiza Abida Ishaq⁵ 

[1] 3billion, Inc, Seoul, Republic of Korea;Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland;Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland;Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland;Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland;Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland;Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland;Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden;School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, 54590, Lahore, Pakistan;Services Hospital Lahore, Lahore, Pakistan;

关键词: Exome sequencing;    Pakistan;    Finland;    Skeletal deformities;    Nodulosis;    Arthropathy;    Longitudinal survey;    MMP2;   

DOI  :  10.1186/s12891-023-06856-2

 received in 2023-03-27, accepted in 2023-09-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMulticentric osteolysis nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder characterized by marked progressive bone loss and joint destruction resulting in skeletal deformities. MONA is caused by MMP2 deficiency. Here we report clinical and molecular analyses of four patients in two families from Pakistan and Finland.MethodsClinical analyses including radiography were completed and blood samples were collected. The extracted DNA was subjected to whole-exome analysis or target gene sequencing. Segregation analyses were performed in the nuclear pedigree. Pathogenicity prediction scores for the selected variants and conservation analyses of affected amino acids were observed.ResultsThe phenotype in the four affected individuals was consistent with multicentric osteolysis or MONA, as the patients had multiple affected joints, osteolysis of hands and feet, immobility of knee joint and progressive bone loss. Long-term follow up of the patients revealed the progression of the disease. We found a novel MMP2 c.1336 + 2T > G homozygous splice donor variant segregating with the phenotype in the Pakistani family while a MMP2 missense variant c.1188 C > A, p.(Ser396Arg) was homozygous in both Finnish patients. In-silico analysis predicted that the splicing variant may eventually introduce a premature stop codon in MMP2. Molecular modeling for the p.(Ser396Arg) variant suggested that the change may disturb MMP2 collagen-binding region.ConclusionOur findings expand the genetic spectrum of Multicentric osteolysis nodulosis and arthropathy. We also suggest that the age of onset of this disorder may vary from childhood up to late adolescence and that a significant degree of intrafamilial variability may be present.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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