ISCU encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of [2Fe-2S] and [4Fe-4S] clusters. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. In one process, the [2Fe-2S] cluster transiently assembles on ISCU and is then transferred to GLRX5 in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process.[7][6][8][9]
ISCU mutations have been found in patients with a mitochondrial myopathy called hereditarymyopathy with lactic acidosis (HML).[11] It is also known as hereditary myopathy with exercise intolerance, Swedish type;[11] myopathy with deficiency of succinate dehydrogenase and aconitase;[11] myoglobinuria due to abnormal glycolysis;[11] myopathy with deficiency of ISCU;[10] Larsson–Linderholm syndrome;[12] and Linderholm myopathy.[13]
Biopsy of skeletal muscle shows deficiency of succinate dehydrogenase and aconitase, abnormal iron deposition and lipid droplet accumulation in the mitochondria. Histochemical studies show impaired respiratory chain complexes I, II, and III, impairing oxidative phosphorylation. Electromyography normal or myopathic increased polyphasic MUAPs. EMG results may be dynamic: more likely to have increased polyphasic MUAPs after exercise.[14] There has been documented temporary restoration of succinate dehydrogenase in regenerating muscle after an episode of rhabdomyolysis; however, the effect does not last.[18]
The disease is limited to muscle, with fibroblasts from skin biopsy being unaffected. As non-muscle tissues are unaffected, this necessitates the need for muscle biopsy when DNA testing using saliva or blood is inconclusive.[19][17]
Genetics
This disorder has been associated with several different mutations and is inherited predominantly in an autosomal recessive manner. It was originally believed to affect only those of northern Swedish ancestry, however the disease has been found in those of Norwegian and Finnish decent as well. The carrier rate in northern Sweden has been estimated at 1:188.[15] ISCU deficiency has been linked to pathogenic variants including intronic variants c.418+382G>C, g.7044G>C,[19] and IVS5+382 G>C[20] as well as a c.149G>A missense mutation in exon 3.[21] The intronic mutations have been suggested to activate a cryptic splice site, resulting in the production of a splice variant that encodes a putatively non-functional protein.[10]
In 2016, an Italian male was found to have a de novoautosomal dominant mutation, c.287G>T (p.Gly96Val) in the ISCU gene, that caused hereditary mitochondrial myopathy with lactic acidosis (HML). This mutation resulted in a similar phenotype as seen in the recessive form of the disease.[17]
^Kollberg G, Melberg A, Holme E, Oldfors A (February 2011). "Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy". Neuromuscular Disorders. 21 (2): 115–20. doi:10.1016/j.nmd.2010.11.010. PMID21196119. S2CID38626230.
^Kollberg G, Tulinius M, Melberg A, Darin N, Andersen O, Holmgren D, Oldfors A, Holme E (August 2009). "Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy". Brain. 132 (Pt 8): 2170–9. doi:10.1093/brain/awp152. PMID19567699.
Acquaviva F, De Biase I, Nezi L, Ruggiero G, Tatangelo F, Pisano C, Monticelli A, Garbi C, Acquaviva AM, Cocozza S (September 2005). "Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2". Journal of Cell Science. 118 (Pt 17): 3917–24. doi:10.1242/jcs.02516. PMID16091420. S2CID6082284.
