ISCA1 Mutation In A Patient With Infantile-Onset Leukodystrophy Causes Defects In Mitochondrial [4Fe-4S] Proteins

Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, Rosalba Carrozzo

Research output: Contribution to journalArticle

Abstract

Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes, and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.

Original languageEnglish
Pages (from-to)2739–2754
Number of pages16
JournalHuman Molecular Genetics
DOIs
Publication statusPublished - Aug 1 2018

Fingerprint

Thioctic Acid
Mutation
Nonketotic Hyperglycinemia
Lactic Acidosis
Proteins
Mitochondrial Proteins
Organelle Biogenesis
Muscular Diseases
Missense Mutation
Mutant Proteins
RNA Interference
HeLa Cells
Respiration
Down-Regulation
Fibroblasts
Phenotype
Enzymes
Genes
Multiple Mitochondrial Dysfunctions Syndrome
Mitochondrial encephalopathy

Cite this

@article{b85c6240757042958068f33bcce28bcd,
title = "ISCA1 Mutation In A Patient With Infantile-Onset Leukodystrophy Causes Defects In Mitochondrial [4Fe-4S] Proteins",
abstract = "Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes, and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.",
author = "Alessandra Torraco and Oliver Stehling and Claudia St{\"u}mpfig and Ralf R{\"o}sser and {De Rasmo}, Domenico and Giuseppe Fiermonte and Daniela Verrigni and Teresa Rizza and Angelo Vozza and {Di Nottia}, Michela and Daria Diodato and Diego Martinelli and Fiorella Piemonte and Carlo Dionisi-Vici and Enrico Bertini and Roland Lill and Rosalba Carrozzo",
year = "2018",
month = "8",
day = "1",
doi = "10.1093/hmg/ddy183",
language = "English",
pages = "2739–2754",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - ISCA1 Mutation In A Patient With Infantile-Onset Leukodystrophy Causes Defects In Mitochondrial [4Fe-4S] Proteins

AU - Torraco, Alessandra

AU - Stehling, Oliver

AU - Stümpfig, Claudia

AU - Rösser, Ralf

AU - De Rasmo, Domenico

AU - Fiermonte, Giuseppe

AU - Verrigni, Daniela

AU - Rizza, Teresa

AU - Vozza, Angelo

AU - Di Nottia, Michela

AU - Diodato, Daria

AU - Martinelli, Diego

AU - Piemonte, Fiorella

AU - Dionisi-Vici, Carlo

AU - Bertini, Enrico

AU - Lill, Roland

AU - Carrozzo, Rosalba

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes, and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.

AB - Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non-ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes, and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild-type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects.

U2 - 10.1093/hmg/ddy183

DO - 10.1093/hmg/ddy183

M3 - Article

C2 - 29767723

SP - 2739

EP - 2754

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

ER -