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El-Hattab, A.W.* ; Dai, H.* ; Almannai, M.* ; Wang, J.* ; Faqeih, E.A.* ; Al Asmari, A.* ; Saleh, M.A.M.* ; Elamin, M.A.O.* ; Alfadhel, M.* ; Alkuraya, F.S.* ; Hashem, M.* ; Aldosary, M.S.* ; Almass, R.* ; Almutairi, F.B.* ; Alsagob, M.* ; Al-Owain, M.* ; Al-Sharfa, S.* ; Al-Hassnan, Z.N.* ; Rahbeeni, Z.* ; Al-Muhaizea, M.A.* ; Makhseed, N.* ; Foskett, G.K.* ; Stevenson, D.A.* ; Gomez-Ospina, N.* ; Lee, C.* ; Boles, R.G.* ; Schrier Vergano, S.A.* ; Wortmann, S.B. ; Sperl, W.* ; Opladen, T.* ; Hoffmann, G.F.* ; Hempel, M.* ; Prokisch, H. ; Alhaddad, B. ; Mayr, J.A.* ; Chan, W.* ; Kaya, N.* ; Wong, L.J.C.*

Molecular and clinical spectra of FBXL4 deficiency.

Hum. Mutat. 38, 1649-1659 (2017)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype–phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Fbxl4 ; Mitochondrial Diseases ; Mitochondrial Dna Depletion ; Mitochondrial Dna Maintenance ; Mtdna
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Journal Human Mutation
Quellenangaben Volume: 38, Issue: 12, Pages: 1649-1659 Article Number: , Supplement: ,
Publisher Wiley
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)