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Abstract
Objective: To present the clinical, molecular, and cell biological findings in a family with an autosomal recessive form of hereditary spastic paraplegia characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN).
Methods: We used a combination of whole-genome linkage analysis and exome sequencing to map the disease locus and to identify the responsible gene. To analyze the physiologic consequences of the disease, we used biochemical and cell biological methods.
Results: Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like phenotype with slow progression into late adulthood. We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene, previously implicated in 2 infants with lethal perinatal encephalomyopathy. This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57. In addition to a severely decreased amount of normal IBA57 messenger RNA, a patient's cells expressed an aberrantly spliced messenger RNA with a premature stop codon. Lymphoblasts contained 10-fold–lower levels of wild-type, but no signs of truncated IBA57 protein. The decrease in functional IBA57 resulted in reduced levels and activities of several mitochondrial [4Fe-4S] proteins, including complexes I and II, while mitochondrial [2Fe-2S] proteins remained normal.
Conclusions: Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.
GLOSSARY
- αKGDH=
- α-ketoglutarate dehydrogenase;
- bp=
- base pair;
- cDNA=
- complementary DNA;
- HSP=
- hereditary spastic paraplegia;
- ISC=
- iron/sulfur cluster;
- LIAS=
- lipoic acid synthase;
- mitoAco=
- mitochondrial aconitase;
- MMDS3=
- multiple mitochondrial dysfunction syndrome 3;
- mRNA=
- messenger RNA;
- NHLBI=
- National Heart, Lung, and Blood Institute;
- PDH=
- pyruvate dehydrogenase;
- SDS-PAGE=
- sodium dodecyl sulfate–polyacrylamide gel electrophoresis;
- SPOAN=
- spastic paraplegia, optic atrophy, and peripheral neuropathy
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received July 27, 2014.
- Accepted in final form October 23, 2014.
- © 2015 American Academy of Neurology
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