This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
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
AAN Members: Sign in with your AAN member credentials (e-mail or 6-digit Member ID number)
Non-AAN Member subscribers: Sign in with subscriber credentials
Log in using your username and password
Purchase access
Disputes & Debates: Rapid online correspondence
NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
- Stay timely. Submit only on articles published within the last 8 weeks.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- 200 words maximum.
- 5 references maximum. Reference 1 must be the article on which you are commenting.
- 5 authors maximum. Exception: replies can include all original authors of the article.
- Submitted comments are subject to editing and editor review prior to posting.