Abstract
Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ~6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.
| Original language | English |
|---|---|
| Article number | ddr071 |
| Pages (from-to) | 1893-1905 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 20 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - May 2011 |
Fingerprint
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16. / Carelli, Valerio; Schimpf, Simone; Fuhrmann, Nico; Valentino, Maria Lucia; Zanna, Claudia; Iommarini, Luisa; Papke, Monika; Schaich, Simone; Tippmann, Sabine; Baumann, Britta; Barboni, Piero; Longanesi, Lora; Rugolo, Michela; Ghelli, Anna; Alavi, Marcel V.; Youle, Richard J.; Bucchi, Laura; Carroccia, Rosanna; Giannoccaro, Maria Pia; Tonon, Caterina; Lodi, Raffaele; Cenacchi, Giovanna; Montagna, Pasquale; Liguori, Rocco; Wissinger, Bernd.
In: Human Molecular Genetics, Vol. 20, No. 10, ddr071, 05.2011, p. 1893-1905.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16
AU - Carelli, Valerio
AU - Schimpf, Simone
AU - Fuhrmann, Nico
AU - Valentino, Maria Lucia
AU - Zanna, Claudia
AU - Iommarini, Luisa
AU - Papke, Monika
AU - Schaich, Simone
AU - Tippmann, Sabine
AU - Baumann, Britta
AU - Barboni, Piero
AU - Longanesi, Lora
AU - Rugolo, Michela
AU - Ghelli, Anna
AU - Alavi, Marcel V.
AU - Youle, Richard J.
AU - Bucchi, Laura
AU - Carroccia, Rosanna
AU - Giannoccaro, Maria Pia
AU - Tonon, Caterina
AU - Lodi, Raffaele
AU - Cenacchi, Giovanna
AU - Montagna, Pasquale
AU - Liguori, Rocco
AU - Wissinger, Bernd
PY - 2011/5
Y1 - 2011/5
N2 - Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ~6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.
AB - Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ~6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.
UR - http://www.scopus.com/inward/record.url?scp=79955368211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955368211&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr071
DO - 10.1093/hmg/ddr071
M3 - Article
C2 - 21349918
AN - SCOPUS:79955368211
VL - 20
SP - 1893
EP - 1905
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 10
M1 - ddr071
ER -