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Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome.
N Engl J Med. 2007 Feb 22; 356(8):809-19.NEJM

Abstract

BACKGROUND

The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36.

METHODS

Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome.

RESULTS

BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species.

CONCLUSIONS

BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.

Authors+Show Affiliations

Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17314340

Citation

Hinson, J Travis, et al. "Missense Mutations in the BCS1L Gene as a Cause of the Björnstad Syndrome." The New England Journal of Medicine, vol. 356, no. 8, 2007, pp. 809-19.
Hinson JT, Fantin VR, Schönberger J, et al. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N Engl J Med. 2007;356(8):809-19.
Hinson, J. T., Fantin, V. R., Schönberger, J., Breivik, N., Siem, G., McDonough, B., Sharma, P., Keogh, I., Godinho, R., Santos, F., Esparza, A., Nicolau, Y., Selvaag, E., Cohen, B. H., Hoppel, C. L., Tranebjaerg, L., Eavey, R. D., Seidman, J. G., & Seidman, C. E. (2007). Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. The New England Journal of Medicine, 356(8), 809-19.
Hinson JT, et al. Missense Mutations in the BCS1L Gene as a Cause of the Björnstad Syndrome. N Engl J Med. 2007 Feb 22;356(8):809-19. PubMed PMID: 17314340.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. AU - Hinson,J Travis, AU - Fantin,Valeria R, AU - Schönberger,Jost, AU - Breivik,Noralv, AU - Siem,Geir, AU - McDonough,Barbara, AU - Sharma,Pankaj, AU - Keogh,Ivan, AU - Godinho,Ricardo, AU - Santos,Felipe, AU - Esparza,Alfonso, AU - Nicolau,Yamileth, AU - Selvaag,Edgar, AU - Cohen,Bruce H, AU - Hoppel,Charles L, AU - Tranebjaerg,Lisbeth, AU - Eavey,Roland D, AU - Seidman,J G, AU - Seidman,Christine E, PY - 2007/2/23/pubmed PY - 2007/3/3/medline PY - 2007/2/23/entrez SP - 809 EP - 19 JF - The New England journal of medicine JO - N Engl J Med VL - 356 IS - 8 N2 - BACKGROUND: The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36. METHODS: Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome. RESULTS: BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species. CONCLUSIONS: BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species. SN - 1533-4406 UR - https://wwww.unboundmedicine.com/medline/citation/17314340/Missense_mutations_in_the_BCS1L_gene_as_a_cause_of_the_Björnstad_syndrome_ L2 - https://www.nejm.org/doi/10.1056/NEJMoa055262?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -