**5. Genetic factors of mitochondrial dysfunction syndromes**

As the names imply, multiple mitochondrial dysfunction syndromes are disease conditions affecting mitochondria and usually lead to reduced function of more than one stages of energy production in the organelle [18]. The genetic factors causing these disorders are associated with the biogenesis of cellular ISC and currently these are the following genes: *ISCA2*, *NFU1*, *IBA57*, and *BOLA3*. More recently, *ISCA1* is also reported to lead a disease resembling MMDS and suggested to be a member of the group [19]. Interestingly, MMDS members appear to be inherited in autosomal recessive mode of inheritance (**Table 1**).

consistent representation of the tracks of NCBI, Ensembl, and UCSC Genome Browsers. The gene has several synonyms such as hIsca, HBLD2, and ISA1, and localizes to mitochondria as

AR: autosomal recessive; IM: inheritance mode; LN: locus number; MIM: Mendelian inheritance in man; MMDS:

**phenotype**

dysfunctions syndrome 1

Hereditary Disorders and Human Mutations of Iron-Sulfur Assembly Genes

dysfunctions syndrome 2 with hyperglycinemia

Multiple mitochondrial dysfunctions syndrome 3

dysfunctions syndrome 4

dysfunctions syndrome 5

**MIM PT#**

http://dx.doi.org/10.5772/intechopen.78006

**IM MIM LN**

241

605711 AR 608100

614299 AR 613183

615330 AR 615316

616370 AR 615317

617613 AR 611006

**Gene Cytoband NCBI Genomic location MMDS-related** 

IBA57 1q42.13 200205 1:228,165,807-

mitochondrial dysfunction syndromes; PT#: phenotype number.

**Table 1.** Genes and related mitochondrial dysfunction syndromes.

NFU1 2p13.3 27247 2:69,396,112-69,438,122 Multiple mitochondrial

BOLA3 2p13.1 388962 2:74,135,400-74,147,911 Multiple mitochondrial

228,182,256

ISCA2 14q24.3 122961 14:74,493,719-74,495,567 Multiple mitochondrial

ISCA1 9q21.33 81689 9:86,264,545-86,282,574 Multiple mitochondrial

Effect of depletion of ISC-related proteins on the maturation of cytosolic 4Fe-4S proteins showed that some mitochondrial Fe/S proteins such as mitochondrial aconitase, SDH, several proteins of complex I, and Rieske Fe/S protein were decreased with the deficiency of ISCA1. On the other hand, cellular heme content and mitochondrial 2Fe-2S ferrochelatase were unaffected by the depletion. This implies that ISCA1 is crucial in the maturation of mitochondrial 4Fe-4S proteins [25]. In another study, *ISCA1* was found to be associated with multiple mitochondrial dysfunctions syndrome-5. A homozygous missense mutation at a conserved residue in the Fe-S biogenesis domain (c.259G>A, p.Glu87Lys) was identified in two unrelated Indian families. This mutation destabilizes the protein subsequently causing

ISCA2 stands for iron-sulfur cluster assembly 2 protein and the gene encodes for A-type ironsulfur cluster protein. Fe-S clusters are inorganic cofactors, mostly found in metalloproteins. The gene is located on chromosome 14 and expressed from the plus strand. According to Ensembl, this gene generates 4 different transcripts and has 96 orthologues. ISCA2 is a regulatory protein found in mitochondria as well as extra mitochondrial sites such as cytosol and nucleus. The protein takes part in assembly of Fe-S clusters in mitochondria which further take part in oxidation reduction (especially in complex 1 and 2), substrate activation, iron/sulfur storage, regulation of gene expression, and enzyme activity. Alternative name for ISCA2 is "HESB-like-domain-containing protein 1" for humans. First human mutation of *ISCA2*

well as cytoplasm.

the syndrome [19].

**5.2. ISCA2**
