Alternative titles; symbols
HGNC Approved Gene Symbol: ISCA2
SNOMEDCT: 1208621008;
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:74,493,765-74,497,106 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Multiple mitochondrial dysfunctions syndrome 4 | 616370 | Autosomal recessive | 3 |
ISCA2, like ISCA1 (611006) and IBA57 (615316), is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria. These 3 proteins function late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins (Sheftel et al., 2012).
Using cell fractionation, immunoblot analysis, and confocal microscopy, Sheftel et al. (2012) demonstrated mitochondrial localization of human ISCA2.
Gross (2013) mapped the ISCA2 gene to chromosome 14q24.3 based on an alignment of the ISCA2 sequence (GenBank BC032893) with the genomic sequence (GRCh37).
Sheftel et al. (2012) used RNA interference to deplete HeLa cells of ISCA1, ISCA2, and IBA57 and observed swollen mitochondria devoid of cristae membranes. Depletion of these proteins also resulted in diminished activities of mitochondrial 4Fe-4S proteins, including aconitase (ACO2; 100850), respiratory complex I (see 602985), and lipoic acid synthase (LIAS; 607031). In contrast, cellular heme content and mitochondrial 2Fe-2S ferrochelatase (FECH; 612386) were unaffected. Sheftel et al. (2012) proposed that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the ISC assembly pathway.
In 6 patients from 5 consanguineous Arab families with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370), Al-Hassnan et al. (2015) identified a homozygous missense mutation in the ISCA2 gene (G77S; 615317.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Patient cells showed decreased expression of ISCA2, ISCA1 (611006), and IBA57 (615316). Functional studies of the ISCA2 variant were not performed, but Al-Hassnan et al. (2015) noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function.
In 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, Alaimo et al. (2018) identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Dermal fibroblasts from 1 of the patients showed diminished mitochondrial membrane potential, variably decreased or increased mitochondrial enzyme complexes, decreased oxygen consumption, and decreased ATP production compared to controls, consistent with mitochondrial dysfunction. There was a decrease in complex II activity and mildly decreased complex IV activity, with intact complexes I and III. The mitochondria also showed morphologic defects as well as decreased mtDNA content, to about 25% of normal values. Patient cells also showed decreased levels of protein lipoylation, indicating a defect in the production of lipoic acid, presumably due to faulty Fe-S cluster generation and specifically affecting the 4Fe-4S-dependent enzyme LIAS (607031). Knockdown of ISCA2 using shRNA resulted in similar cellular abnormalities and defects involving 4Fe-4S-dependent proteins, but not 2Fe-2S proteins.
In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, Alfadhel et al. (2018) identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster.
In an Italian infant with MMDS4, Toldo et al. (2018) identified compound heterozygous mutations in the ISCA2 gene (c.295delT, 615317.0002 and S112G, 615317.0003). The mutations, which were found by next-generation sequencing of a panel of genes associated with mitochondrial disorders, segregated with the disorder in the family. Functional studies of the variant were not performed.
In 6 patients from 5 consanguineous Arab families with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370), Al-Hassnan et al. (2015) identified a homozygous c.229G-A transition in exon 3 of the ISCA2 gene (d.G74961032A), resulting in a gly77-to-ser (G77S) substitution at highly conserved residues in the Fe-S domain. The mutation, which was found by a combination of autozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 1,060 chromosomes from ethnically matched controls. Haplotype analysis indicated a founder effect estimated to have occurred 4,802 years ago. Functional studies of the ISCA2 variant were not performed, but Al-Hassnan et al. (2015) noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function.
In 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, Alaimo et al. (2018) identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families.
In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, Alfadhel et al. (2018) identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster.
In an Italian infant with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370), Toldo et al. (2018) identified compound heterozygous mutations in the ISCA2 gene: a 1-bp deletion (c.295delT), predicted to result in a frameshift and premature termination (Phe99LeufsTer18), and a c.334A-G transition, resulting in a ser112-to-gly (S112G; 615317.0003) substitution. The mutations, which were found by next-generation sequencing of a panel of genes associated with mitochondrial disorders, segregated with the disorder in the family. Functional studies of the variant were not performed.
For discussion of the c.334A-G transition in the ISCA2 gene, resulting in a ser112-to-gly (S112G) substitution, that was found in compound heterozygous state in a patient with multiple mitochondrial dysfunctions syndrome-4 (MMDS4; 616370) by Toldo et al. (2018), see 615317.0002.
Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J. Med. Genet. 52: 186-194, 2015. [PubMed: 25539947] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102592]
Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E. Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion. Hum. Mutat. 39: 537-549, 2018. [PubMed: 29297947] [Full Text: https://doi.org/10.1002/humu.23396]
Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N. Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases. Europ. J. Paediat. Neurol. 22: 46-55, 2018. [PubMed: 29122497] [Full Text: https://doi.org/10.1016/j.ejpn.2017.10.003]
Gross, M. B. Personal Communication. Baltimore, Md. 7/18/2013.
Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. Molec. Biol. Cell 23: 1157-1166, 2012. [PubMed: 22323289] [Full Text: https://doi.org/10.1091/mbc.E11-09-0772]
Toldo, I., Nosadini, M., Boscardin, C., Talenti, G., Manara, R., Lamantea, E., Legati, A., Ghezzi, D., Perilongo, G., Sartori, S. Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations. Metab. Brain Dis. 33: 805-812, 2018. [PubMed: 29359243] [Full Text: https://doi.org/10.1007/s11011-017-0181-3]