Artikel
A novel homozygous frameshift mutation in LACC1 associated with severe familial forms of juvenile idiopathic arthritis
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Veröffentlicht: | 29. August 2016 |
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Background: The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, recently a homozygous missense mutation c.850T>C in LACC1 has been reported in several patients with therapy-refractory systemic JIA (sJIA) from consanguineous families in Saudi Arabia.
We here describe two siblings from a large consanguineous Lebanese family with severe JIA harboring a novel homozygous LACC1 mutation.
Methods: One child presented with sJIA at 16 month of age and clinical remission was achieved 3.5 years after the introduction of tocilizumab. Acute lymphatic leukemia (ALL) was diagnosed with six years and was treated according to the AIEOP-BFMALL 2009 protocol. Two years later, an early combined ALL relapse occurred. Treatment according to the ALL-REZ BFM 2002 protocol including allogeneic stem cell transplantation was applied. The younger sister developed extended-oligoarticluar JIA with markedly increased inflammation markers at age 15 months. Low disease activitiy was achieved by a combination of adalimumab, methotrexate and hydroxychloroquin. Other family members never presented with signs of chronic inflammation.
Whole-exome sequencing (WES) was performed on DNA samples of two index patients and both parents. Sequence variants were filtered for a recessive mode of inheritance (homozygous and compound heterozygous) in GeneTalk to identify candidate variants. Candidate gene variants were validated via Sanger sequencing.
Results: Whole exome sequencing revealed a novel, homozygous one base pair deletion in LACC1 (NM_153218.2:c.827delC) in the affected children. Both parents are heterozygous carriers; two unaffected children carry wildtype alleles. The mutation results in a frameshift p.(Thr276Lysfs*2) with a premature stop at position 278. Its location in the fourth out of 7 exons is designated to cause to nonsense-mediated mRNA decay with loss of enzymatic activity.
Conclusion: We here present a consanguineous family with 2 affected individuals suffering of severe forms of JIA associated with a novel mutation in LACC1. Together with the previously described cases of LACC1-associated familial systemic JIA and the reported association with other inflammatory and infectious diseases, the present cases add evidence that LACC1 is a recessive disease gene and its loss of function results in a familial JIA phenotype.