A Genomewide Linkage-disequilibrium Scan Localizes the Saguenay-Lac-Saint-Jean Cytochrome Oxidase Deficiency to 2p16

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2001 Jan 13

PMID 11156535

Citations 12

Authors

N Lee

M J Daly

T Delmonte

E S Lander

F Xu

T J Hudson

G A Mitchell

C C Morin

B H Robinson

J D Rioux

Affiliations

Soon will be listed here.

Abstract

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.

Citing Articles

Expression signature of the Leigh syndrome French-Canadian type.

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References

Zhu Z, Yao J, Johns T, Fu K, De Bie I, MacMillan C . SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998; 20(4):337-43. DOI: 10.1038/3804. View

Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P . Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998; 93(6):973-83. DOI: 10.1016/s0092-8674(00)81203-9. View

Morin C, Dube J, Robinson B, Lacroix J, Michaud J, De Braekeleer M . Stroke-like episodes in autosomal recessive cytochrome oxidase deficiency. Ann Neurol. 1999; 45(3):389-92. View

Montpetit V, Andermann F, Carpenter S, Fawcett J, Giberson H . Subacute necrotizing encephalomyelopathy. A review and a study of two families. Brain. 1971; 94(1):1-30. DOI: 10.1093/brain/94.1.1. View

Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M . Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet. 1998; 63(6):1609-21. PMC: 1377632. DOI: 10.1086/302150. View

Richter A, Rioux J, Bouchard J, Mercier J, Mathieu J, Ge B . Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11. Am J Hum Genet. 1999; 64(3):768-75. PMC: 1377794. DOI: 10.1086/302274. View

Morin C, Mitchell G, Larochelle J, Lambert M, Ogier H, Robinson B . Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet. 1993; 53(2):488-96. PMC: 1682365. View

Kruglyak L . Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999; 22(2):139-44. DOI: 10.1038/9642. View

Watanabe T, Inoue S, Hiroi H, Orimo A, Kawashima H, Muramatsu M . Isolation of estrogen-responsive genes with a CpG island library. Mol Cell Biol. 1998; 18(1):442-9. PMC: 121513. DOI: 10.1128/MCB.18.1.442. View

10.

Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E . Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet. 1995; 11(2):144-9. DOI: 10.1038/ng1095-144. View

11.

Robinson B . Lacticacidemia. Biochim Biophys Acta. 1993; 1182(3):231-44. DOI: 10.1016/0925-4439(93)90064-8. View

12.

Lee N, Morin C, Mitchell G, Robinson B . Saguenay Lac Saint Jean cytochrome oxidase deficiency: sequence analysis of nuclear encoded COX subunits, chromosomal localization and a sequence anomaly in subunit VIc. Biochim Biophys Acta. 1998; 1406(1):1-4. DOI: 10.1016/s0925-4439(98)00003-9. View

13.

Heyer E . One founder/one gene hypothesis in a new expanding population: Saguenay (Quebec, Canada). Hum Biol. 1999; 71(1):99-109. View

14.

Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V . Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet. 2000; 67(5):1104-9. PMC: 1288552. DOI: 10.1016/S0002-9297(07)62940-1. View

15.

De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard J, Morgan K . Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec. Genet Epidemiol. 1993; 10(1):17-25. DOI: 10.1002/gepi.1370100103. View

16.

McEachern G, Raha S, Tarnopolsky M, Turnbull J, Bourgeois J, Robinson B . Manganese superoxide dismutase levels are elevated in a proportion of amyotrophic lateral sclerosis patient cell lines. Biochem Biophys Res Commun. 2000; 273(1):359-63. DOI: 10.1006/bbrc.2000.2933. View

17.

Pitkanen S, Robinson B . Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J Clin Invest. 1996; 98(2):345-51. PMC: 507436. DOI: 10.1172/JCI118798. View

18.

Dahl H . Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. Am J Hum Genet. 1998; 63(6):1594-7. PMC: 1377630. DOI: 10.1086/302169. View

19.

Hastbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, LANDER E . Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992; 2(3):204-11. DOI: 10.1038/ng1192-204. View

20.

Merante F, Mackay N, Mitchell G, Lambert M, Morin C, De Braekeleer M . A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec. Am J Hum Genet. 1993; 53(2):481-7. PMC: 1682348. View