Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes

Sze Chern Lim, Martin Friemel, Justine E. Marum, Elena J. Tucker, Damien L. Bruno, Lisa G. Riley, John Christodoulou, Edwin P. Kirk, Avihu Boneh, Christine M. DeGennaro, Michael Springer, Vamsi K. Mootha, Tracey A. Rouault, Silke Leimkühler, David R. Thorburn, Alison G. Compton

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Abstract

Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-Sproteins) are present inmitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe- S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the L-cysteine desulfurase activityofNFS1was barely presentwhenco-expressed with mutant ISD11.Ourfindings are consistent with a defect in the early step of ISCassemblyaffecting abroad variety of Fe-Sproteins.Thedifferences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.

Original languageEnglish
Article numberddt295
Pages (from-to)4460-4473
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number22
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

Cite this

Lim, S. C., Friemel, M., Marum, J. E., Tucker, E. J., Bruno, D. L., Riley, L. G., ... Compton, A. G. (2013). Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Human Molecular Genetics, 22(22), 4460-4473. [ddt295]. https://doi.org/10.1093/hmg/ddt295
Lim, Sze Chern ; Friemel, Martin ; Marum, Justine E. ; Tucker, Elena J. ; Bruno, Damien L. ; Riley, Lisa G. ; Christodoulou, John ; Kirk, Edwin P. ; Boneh, Avihu ; DeGennaro, Christine M. ; Springer, Michael ; Mootha, Vamsi K. ; Rouault, Tracey A. ; Leimkühler, Silke ; Thorburn, David R. ; Compton, Alison G. / Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 22. pp. 4460-4473.
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title = "Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes",
abstract = "Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-Sproteins) are present inmitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe- S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the L-cysteine desulfurase activityofNFS1was barely presentwhenco-expressed with mutant ISD11.Ourfindings are consistent with a defect in the early step of ISCassemblyaffecting abroad variety of Fe-Sproteins.Thedifferences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.",
author = "Lim, {Sze Chern} and Martin Friemel and Marum, {Justine E.} and Tucker, {Elena J.} and Bruno, {Damien L.} and Riley, {Lisa G.} and John Christodoulou and Kirk, {Edwin P.} and Avihu Boneh and DeGennaro, {Christine M.} and Michael Springer and Mootha, {Vamsi K.} and Rouault, {Tracey A.} and Silke Leimk{\"u}hler and Thorburn, {David R.} and Compton, {Alison G.}",
year = "2013",
month = "11",
doi = "10.1093/hmg/ddt295",
language = "English",
volume = "22",
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Lim, SC, Friemel, M, Marum, JE, Tucker, EJ, Bruno, DL, Riley, LG, Christodoulou, J, Kirk, EP, Boneh, A, DeGennaro, CM, Springer, M, Mootha, VK, Rouault, TA, Leimkühler, S, Thorburn, DR & Compton, AG 2013, 'Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes', Human Molecular Genetics, vol. 22, no. 22, ddt295, pp. 4460-4473. https://doi.org/10.1093/hmg/ddt295

Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. / Lim, Sze Chern; Friemel, Martin; Marum, Justine E.; Tucker, Elena J.; Bruno, Damien L.; Riley, Lisa G.; Christodoulou, John; Kirk, Edwin P.; Boneh, Avihu; DeGennaro, Christine M.; Springer, Michael; Mootha, Vamsi K.; Rouault, Tracey A.; Leimkühler, Silke; Thorburn, David R.; Compton, Alison G.

In: Human Molecular Genetics, Vol. 22, No. 22, ddt295, 11.2013, p. 4460-4473.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes

AU - Lim, Sze Chern

AU - Friemel, Martin

AU - Marum, Justine E.

AU - Tucker, Elena J.

AU - Bruno, Damien L.

AU - Riley, Lisa G.

AU - Christodoulou, John

AU - Kirk, Edwin P.

AU - Boneh, Avihu

AU - DeGennaro, Christine M.

AU - Springer, Michael

AU - Mootha, Vamsi K.

AU - Rouault, Tracey A.

AU - Leimkühler, Silke

AU - Thorburn, David R.

AU - Compton, Alison G.

PY - 2013/11

Y1 - 2013/11

N2 - Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-Sproteins) are present inmitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe- S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the L-cysteine desulfurase activityofNFS1was barely presentwhenco-expressed with mutant ISD11.Ourfindings are consistent with a defect in the early step of ISCassemblyaffecting abroad variety of Fe-Sproteins.Thedifferences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.

AB - Iron-sulfur clusters (ISCs) are important prosthetic groups that define the functions of many proteins. Proteins with ISCs (called iron-sulfur or Fe-Sproteins) are present inmitochondria, the cytosol, the endoplasmic reticulum and the nucleus. They participate in various biological pathways including oxidative phosphorylation (OXPHOS), the citric acid cycle, iron homeostasis, heme biosynthesis and DNA repair. Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency. LYRM4 encodes the ISD11 protein, which forms a complex with, and stabilizes, the sulfur donor NFS1. The homozygous mutation (c.203G>T, p.R68L) was identified via massively parallel sequencing of >1000 mitochondrial genes (MitoExome sequencing) in a patient with deficiency of complexes I, II and III in muscle and liver. These three complexes contain ISCs. Sanger sequencing identified the same mutation in his similarly affected cousin, who had a more severe phenotype and died while a neonate. Complex IV was also deficient in her skeletal muscle. Several other Fe- S proteins were also affected in both patients, including the aconitases and ferrochelatase. Mutant ISD11 only partially complemented for an ISD11 deletion in yeast. Our in vitro studies showed that the L-cysteine desulfurase activityofNFS1was barely presentwhenco-expressed with mutant ISD11.Ourfindings are consistent with a defect in the early step of ISCassemblyaffecting abroad variety of Fe-Sproteins.Thedifferences in biochemical and clinical features between the two patients may relate to limited availability of cysteine in the newborn period and suggest a potential approach to therapy.

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U2 - 10.1093/hmg/ddt295

DO - 10.1093/hmg/ddt295

M3 - Article

VL - 22

SP - 4460

EP - 4473

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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