Complement factor I deficiency: a not so rare immune defect. Characterization of new mutations and the first large gene deletion

Alba-Domínguez, María; López‐Lera, Alberto; Garrido, Sofía; Nozal, Pilar; González-Granado, Ignacio; Melero, Josefa; Soler‐Palacín, Pere; Cámara, Carmen; López-Trascasa, Margarita

doi:10.1186/1750-1172-7-42

Cited by 57 publications

(41 citation statements)

References 34 publications

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“…In-frame deletions that respect the heptad pattern permit for formation of hybrid repeats, and triple coiling may occur. The alpha helix may form in fractional repeats, but triple coiling does not occur due to the absence of a heptad pattern 31. These differences in structure of mutant truncated dystrophin might account for the variability in the phenotypes of BMD and DMD.…”

Section: Discussionmentioning

confidence: 99%

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

et al. 2017

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Background and PurposeStudies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India.MethodsA retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India.ResultsThe 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found.ConclusionsThe reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

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Section: Discussionmentioning

confidence: 99%

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

et al. 2017

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“…Many of the CFI mutations found in aHUS lead to impaired secretion or function [68, 69]. Recently, larger deletions containing all or part of CFI have also been described [70, 71]. …”

Section: Atypical Hemolytic Uremic Syndrome (Ahus)mentioning

confidence: 99%

Complementopathies

Baines

Brodsky

2017

Blood Reviews

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The complement system is an essential part of the innate immune system that requires careful regulation to ensure responses are appropriately directed against harmful pathogens, while preventing collateral damage to normal host cells and tissues. While deficiency in some components of the complement pathway is associated with increased susceptibility to certain infections, it has also become clear that inappropriate activation of complement is an important contributor to human disease. A number of hematologic disorders are driven by complement, and these disorders may be termed “complementopathies”. This includes paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), cold agglutinin disease (CAD) and other related disorders, which will be the focus of this review. A better understanding of the central role of the complement system in the pathophysiology of these disorders may allow for application of therapies directed at blocking the complement cascade.

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“…30% of patients with factor I mutations also have mutations in other genes encoding complement-regulatory proteins [45] . Recent molecular studies demonstrated four novel mutations in a cohort of screened individuals; among them, the first major gene deletion in the CFI locus was described [76] .…”

Section: Factor I Mutationsmentioning

confidence: 99%

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

114

111

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Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

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Complement factor I deficiency: a not so rare immune defect. Characterization of new mutations and the first large gene deletion

Cited by 57 publications

References 34 publications

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort

Complementopathies

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

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