Abstract
Mevalonate kinase deficiency (MKD) is an autosomal recessive inflammatory disease. Mutations in MVK gene are associated with MKD with modest genotype–phenotype correlation. In spite of recent guidelines indicating specific MVK mutations for the more severe form or the milder one, little is known about MVK variability within and between populations. The aim of this work is to provide supplementary information about MVK variability useful in the molecular diagnosis of MKD, as well as to unravel the presence of novel genes potentially involved as involved in the clinical heterogeneity of MKD phenotype. We used a population-based approach, coupled with Combined Annotation–Dependent Depletion (CADD) score, to analyze the level of genetic variability for common and putatively deleterious MVK variants. We also performed Exome screening with the Illumina Human Exome Bead Chip on 21 MKD patients to double-check our in silico findings. Haplotype block detection in different populations revealed the existence of two blocks in MVK; interestingly, the first haploblock comprises the promoter region shared with MMAB gene. Analyses of MMAB and MVK genetic variants in 21 MKD patients strengthen our observations showing a novel scenario in which the same mutations commonly associated with MKD are found coupled with different combination of MMAB rs7134594 SNP was already described as associated with HDL cholesterol level and present in the haploblock promoter region. The rs7134594 SNP is reported as an eQTL for MVK and MMAB. Hypothesizing the presence of genetic variants modulating the complex phenotypic spectrum of MKD, we suggest that future directions in screening for MKD pathogenic variants should focus both MMAB and MVK genes.
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We are grateful to the patients for participating in this study.
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MM, FC, PMT and SC designed the experimental plan and wrote the manuscript; MM performed the global variation research analysis; RRM and SC performed the exome screening; MM and RRM carried out the statistical analysis; PMT and SC revised the language grammar and style. All authors read and approved the final manuscript.
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RRM was supported by the Grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (BEX-7711/15-8). The study was supported by the “Ricerca Corrente” Grants from IRCCS Burlo Garofolo RC42/11 and RC 13/08.
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Massimo Mezzavilla, Ronald Rodrigues Moura, Fulvio Celsi, Paola Maura Tricarico, and Sergio Crovella declare no conflict of interest.
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The Ethical Committee of IRCCS Burlo Garofolo approved the research (protocol no. 185/08, 19/08/2008).
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Mezzavilla, M., Moura, R.R., Celsi, F. et al. MMAB, a novel candidate gene to be screened in the molecular diagnosis of Mevalonate Kinase Deficiency. Rheumatol Int 38, 121–127 (2018). https://doi.org/10.1007/s00296-017-3890-3
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DOI: https://doi.org/10.1007/s00296-017-3890-3