SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
Autor: | Göran Hallmans, Patrik Rydén, Johan Wikström, Therese G. Kellgren, Adam Ameur, Miep H. Helfrich, Joakim Klar, Niklas Dahl, Torsten Lönnerholm, Petra Henning, Per-Erik Sandström, Emma McDermott, Christina Stecksén-Blicks, Ulf H. Lerner, Fraser P. Coxon, Eva-Lena Stattin |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Medicin och hälsovetenskap Science Osteoclasts Gene mutation Medical and Health Sciences Article Frameshift mutation 03 medical and health sciences Osteoclast medicine Humans Frameshift Mutation Sorting Nexins Exome sequencing Sweden Multidisciplinary Splice site mutation biology Whole Genome Sequencing business.industry RANK Ligand Osteopetrosis Increased Bone Density medicine.disease 3. Good health 030104 developmental biology medicine.anatomical_structure Haplotypes RANKL Codon Nonsense biology.protein Medicine business |
Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) |
Popis: | Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro. |
Databáze: | OpenAIRE |
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