Abstract
The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III (CIII). A homozygous point mutation (232A→G) has been found as the genetic etiology for fetal growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome (MIM 603358). Variable phenotypes have been found with other mutations. Our aim was to assess whether 232A→G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder. A further aim was to confirm the GRACILE genotype–phenotype constancy (n = 8). Three new cases with homozygous 232A→G mutation were identified; all had the primary GRACILE characteristics. No other mutations were found in the gene in other cases. All infants with GRACILE syndrome had the typical mutation. In conclusion, the rather homogenous population of Finns seems to have a specific BCS1L mutation that, as homozygous state, causes GRACILE syndrome, whereas other mutations are rare or not occurring. Thus, the novel clinical implication of this study is to screen for BCS1L mutations only if CIII is dysfunctioning or lacking Rieske protein, and to assess 232A→G mutation in cases with GRACILE syndrome.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Cruciat CM, Hell K, Fölsch H, Neupert W, Stuart RA (1999) Bcs1p, an AAAfamily member, is a chaperone for the assembly of the cytochrome bc1 complex. Embo J 18:226–233
D´Aurelio M, Gajewski CD, Lenaz G, Manfredi G (2006) Respiratory chain supercomplexes set the threshold for respiration defects in human mtDNA mutant cybrids. Hum Mol Genet 15:2157–2169
De Lonlay P, Valnot I, Barrientos A, Gorbatyuk M, Tzagoloff A, Taanman JW, Benayoun E, Chretien D, Kadhom N, Lombes A, de Baulny HO, Niaudet P, Munnich A, Rustin P, Rötig A (2001) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 29:57–60
De Meirleir L, Seneca S, Damis E, Sepulchre B, Hoorens A, Gerlo E, Garcia Silva MT, Hernandez EM, Lissens W, Van Coster R (2003) Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. Am J Med Genet 121:126–131
Di Mauro S, Schon EA (2003) Mechanisms of disease: mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668
Dipple KM, McCabe ER (2000) Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 71:43–50
Dipple KM, Phelan JK, McCabe ER (2001) Consequences of complexity within biological networks: robustness and health, or vulnerability and disease. Mol Genet Metab 74:45–50
Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998) Iron overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351:490–493
Fellman V (2002) The GRACILE syndrome, a neonatal lethal metabolic disorders with iron overload. Blood Cells Mol Dis 29:444–450
Fellman V, Visapää I, Vujic M, Wennerholm U-B, Peltonen L (2002) Antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria, cholestasis, iron overload, and lactic acidosis in the newborn infant. Acta Obstetr Gynecol Scand 81:398–402
Fellman V (2006) Respiratory complex III deficiencies in the newborn infant. Drug Disc Dis Mech 3:421–427
Fernandez-Vizarra E, Bugiani M, Goffrini P, Carrara F, Farina L, Procopio E, Donati A, Uziel G, Ferrero I, Zeviani M (2007) Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum Mol Genet 6:1241–1252
Haut S, Brivet M, Touati G, Rustin P, Lebon S, Garcia-Cazorla A, Saudubray JM, Boutron A, Legrand A, Slama A (2003) A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis. Hum Genet 113:118–122
Hinson JT, Fantin VR, Schonberger J, Breivik N, Siem G, McDonough B, Sharma P, Keogh I, Godinho R, Santos F, Esparza A, Nicolau Y, Selvaag E, Cohen BH, Hoppel CL, Tranebjaerg L, Eavey RD, Seidman JG, Seidman CE (2007) Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. N Engl J Med 356:809–819
Kotarsky H, Imran T, Mannisto S, Heikinheimo M, Hansson S, Fellman V (2007) BCS1L is expressed in critical regions for neural development during ontogenesis in mice. Gen Expr Patterns 3:266–273
Morris AAM, Taylor RW, Birch-Manin MA, Jackson MJ, Coulthard MG, Bindoff LA, Welch RJ, Howell N, Turnbull DM (1995) Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain. Pediatr Nephrol 9:407–411
Nobrega FG, Nobrega MP, Tzagoloff A (1992) BCS1, a novel gene required for the expression of functional Rieske iron-sulfur protein in Saccharomyces cerevisiae. Embo J 11:3821–3829
Norio R (2003) Finnish disease heritage I: characteristics, causes, background. Hum Genet 112:441–456
Robinson BH (2006) Lactic acidemia and mitochondrial disease. Mol Genet Metab 89:3–13
Scaglia F, Towbin JA, Craigen WJ, Belmont JW, O´Brian Smith E, Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutiu GD, Wong LJC, Vogel H (2004) Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114:925–931
Syvänen AC, Aalto-Setala K, Harju L, Kontula K, Soderlund H (1990) A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics 8:684–692
Valnot I, Kassis J, Chretien D, de Lonlay P, Parfait B, Munnich A, Kachaner J, Rustin P, Rotig A (1999) A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency. Hum Genet 104:460–406
Van Coster R, Smet J, George E, De Meirleir L, Seneca S, Van Hove J, Sebire G, Verhelst H, De Bleecker J, Van Vlelm B, Verloo P, Leroy J (2001) Blue native polyacrylamide gel electrophoresis: a powerful tool in diagnosis of oxidative phosphorylation defects. Pediatr Res 50:658–665
Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 4:863–876
Acknowledgments
We acknowledge Kari Raivio and Tuula Lönnqvist for providing DNA from some patients.
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interest: nothing to disclose. Funding: the study was supported by grants from Medical Society of Finland (Finska Läkaresällskapet).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Fellman, V., Lemmelä, S., Sajantila, A. et al. Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause. J Hum Genet 53, 554–558 (2008). https://doi.org/10.1007/s10038-008-0284-0
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-008-0284-0
Keywords
This article is cited by
-
Complex III staining in blue native polyacrylamide gels
Journal of Inherited Metabolic Disease (2011)
-
Les cholestases néonatales
Revue de médecine périnatale (2010)
-
Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases
BMC Medical Genomics (2009)
