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Leigh Syndrome Associated with a Mutation in the NDUFS7 (PSST) Nuclear Encoded Subunit of Complex I

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Leigh Syndrome Associated with a Mutation in the NDUFS7 (PSST) Nuclear Encoded Subunit of Complex I UvA-DARE (Digital Academic Repository) Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I Triepels, R.H.; van den Heuvel, L.P.; Loeffen, J.L.C.M.; Buskens, C.A.F.; Smeets, R.J.P.; Rubio Gozalbo, M.E.; Budde, S.M.S.; Mariman, E.C.; Wijburg, F.A.; Barth, P.G.; Trijbels, J.M.F.; Smeitink, J.A.M. DOI 10.1002/1531-8249(199906)45:6<787::AID-ANA13>3.0.CO;2-6 Publication date 1999 Published in Annals of Neurology Link to publication Citation for published version (APA): Triepels, R. H., van den Heuvel, L. P., Loeffen, J. L. C. M., Buskens, C. A. F., Smeets, R. J. P., Rubio Gozalbo, M. E., Budde, S. M. S., Mariman, E. C., Wijburg, F. A., Barth, P. G., Trijbels, J. M. F., & Smeitink, J. A. M. (1999). Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Annals of Neurology, 45, 787- 790. https://doi.org/10.1002/1531-8249(199906)45:6<787::AID-ANA13>3.0.CO;2-6 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You UvA-DAREwill be contacted is a service as provided soon as by possible.the library of the University of Amsterdam (https://dare.uva.nl) Download date:02 Oct 2021 BRIEF COMMUNICATIONS result of mutations in the nuclear encoded complex I Leigh Syndrome Associated subunits. with a Mutation in the To obtain more insight in the contribution of nu- clear complex I genes to dysfunction of the complex, NDUFS7 (PSST) Nuclear we started a mutational detection program for nuclear complex I genes in complex I–deficient patients. Nu- Encoded Subunit of clear genes already present in the minimal form of complex I of Escherichia coli and genes coding for pro- Complex I teins displaying a theoretically important role in the R. H. Triepels, MSc,* L. P. van den Heuvel, PhD,* function of the complex4 were the first to be analyzed. J. L. C. M. Loeffen, MD,* C. A. F. Buskens, MSc,* The mutational detection study of the human nu- R. J. P. Smeets, BSc,* M. E. Rubio Gozalbo,* clear encoded complex I subunit NDUFS7,5 the NuoB S. M. S. Budde,* E. C. Mariman,† 6 F. A. Wijburg, MD, PhD,‡ P. G. Barth, MD, PhD,‡ subunit counterpart of E. coli, revealed a valine to me- J. M. F. Trijbels, PhD,* and J. A. M. Smeitink, MD, PhD* thionine amino acid substitution that cosegregated in a neuropathologically proven Leigh syndrome family with complex I deficiency. Leigh syndrome is the phenotypical expression of a ge- netically heterogeneous cluster of disorders, with pyru- vate dehydrogenase complex deficiency and respiratory Patient Report chain disorders as the main biochemical causes. We re- A study of a patient with complex I–deficient neuropatho- logically proven Leigh syndrome without lactic acidosis was port the first missense mutation within the nuclear en- 7 coded complex I subunit, NDUFS7, in 2 siblings with published in 1991. The nonconsanguineous parents were neuropathologically proven complex I–deficient Leigh Dutch. syndrome. The second boy in this family developed, from the age of 11 months, periodic but otherwise unexplained vomiting. Triepels RH, van den Heuvel LP, From the age of about 3 years, a progressive deterioration Loeffen JLCM, Buskens CAF, Smeets RJP, was noted. He developed left-sided hemiplegia, dysarthria Rubio Gozalbo ME, Budde SMS, Mariman EC, and an abnormal breathing pattern with regularly deep Wijburg FA, Barth PG, Trijbels JMF, breaths, and severe feeding difficulties requiring tube feeding. Smeitink JAM. Leigh syndrome associated with a There was generalized hypotonia at rest and increased tendon mutation in the NDUFS7 (PSST) nuclear reflexes. As in the case of his brother, measurements of lac- encoded subunit of complex I. tate and pyruvate concentrations in urine, blood, and cere- Ann Neurol 1999;45:787–790 brospinal fluid were repeatedly normal. An oral glucose load- ing test (2 g/kg of body weight) showed no pathological increment of lactate, pointing to a normal cytosolic redox NADH:ubiquinone oxidoreductase (complex I), the status. A long-chain triglyceride loading test (1.5 ml/kg of largest of the four respiratory chain complexes, trans- body weight) revealed normal ketone body ratios, indicating fers electrons with a high redox potential from NADH a normal mitochondrial redox status. to ubiquinone.1 Electroencephalogram and visual evoked potentials were normal. Brain acoustical evoked response showed a low 5th Complex I deficiency is frequently encountered. Al- potential after right acoustic stimulation. Brain magnetic res- though the age at onset and course of this disease may onance imaging showed bilateral putaminal, caudate, and vary, many complex I–deficient patients suffer from a 2 dentate lesions, and lesions of the left cerebral peduncle and progressive, often early fatal multisystem disorder, fre- right paramedian area of the medulla oblongata with en- 3 quently Leigh syndrome. The genetic causes of com- hanced T2 signal. The patient died at 5 years of age. plex I–deficient patients, in which mitochondrial DNA (mtDNA) mutations have been excluded, may be the Patients and Methods Patient Investigations Our patient study group consists of 20 children with isolated From the *Nijmegen Center for Mitochondrial Disorders, Depart- decreased biochemical complex I activity in skeletal muscle ment of Pediatrics, University Children’s Hospital, and †Depart- tissue and cultured skin fibroblasts.8–10 ment of Human Genetics, University Hospital Nijmegen, Nijme- gen; and ‡Department of Pediatrics, Academic Medical Center, To exclude large mtDNA rearrangements, we analyzed the University of Amsterdam, Amsterdam, The Netherlands. entire mitochondrial genome with a previously developed long template polymerase chain reaction (PCR) technique.11 Received Oct 7, 1998, and in revised form Jan 25, 1999. Accepted for publication Jan 25, 1999. We screened the mitochondrial genome of the patients for the mtDNA mutations T14484C, G14459A, G11778A, Address correspondence to Dr van den Heuvel, Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, University T4160C, G3460A, T8993G/C, T8356C, A8344G, Children’s Hospital Nijmegen, Geert Grooteplein 20, PO Box A4317G, T3271C, and A3243G. On the nuclear level, mu- 9101, 6500 HB Nijmegen, The Netherlands. tational detection of patient fibroblast cDNA of other possi- Copyright © 1999 by the American Neurological Association 787 ble candidate genes (NDUFA1, NDUFB6, NDUFS4, Mutational Detection of the NDUFS7 cDNA NDUFS5, and NDUFS8) was performed by direct DNA For mutational detection of the NDUFS7, we analyzed sequencing. patient cDNA, produced by first-strand synthesis of cultured fibroblast RNA. By using the oligonucleotide Mutational Detection in the NDUFS7 cDNA primers NDUFS7-F and R (see Table 1), we amplified Mutational detection was performed as described previous- 12 5 a 775-bp cDNA PCR fragment containing the com- ly. For PCR amplification of the human NDUFS7 plete NDUFS7 open reading frame. Direct sequencing cDNA, the forward primer as well as the reverse primer (Ta- of the obtained fragment revealed a homozygous ble 1), homologous to the 5Ј and 3Ј untranslated regions, were designed according to human EST (Expressed Sequence G364A transition in 1 patient (Sibling 2), which results Tags),13 and interior primers were ordered according to the in a V122M amino acid substitution. The G364A published NDUFS7 cDNA sequence. transition creates a Bcl I restriction site. Analysis of cDNA produced by first-strand synthesis of RNA of Tissue Distribution of NDUFS7 mRNA both parents and a younger affected brother (Sibling 1) To obtain more information concerning mRNA quantities of revealed that this mutations is consistent with an auto- the human NDUFS7 in a wide range of human tissues, we somal recessive mode of inheritance (Fig). The G364A used a human poly(A)ϩ RNA Master Blot (Clontech, Mad- mutation was not present in 60 Dutch control alleles ison, WI). Hybridization was performed according to estab- and another 19 complex I–deficient patients, including lished procedures by using [␣-32P]dCTP-labeled wild-type 5 patients displaying the clinical phenotype of Leigh cDNA PCR fragment containing the NDUFS7 open reading 10 syndrome. frame. Afterward the blot was analyzed by autoradiography. In addition, a T68C transition, introducing a MspI restriction site on the DNA level and a L23P amino Results acid substitution on the protein level, was observed. Genetic Analysis of the Patient Group MspI restriction analysis revealed an allelic frequency of Amplification of the entire mitochondrial genome of this transition of 37.5% in 19 isolated complex I– all patients showed no large mtDNA deletions or in- deficient patients and 35% in 60 control alleles. sertions. None of the investigated mtDNA abnormali- ties were detected. Two mutations in nuclear encoded complex I subunits were found, a 5-bp duplication in Tissue Distribution of NDUFS7 Transcripts the NDUFS4 subunit in a non-Leigh syndrome com- In descending order, the ubiquitously expressed plex I–deficient patient12 and a compound heterozy- NDUFS7 mRNA was extensively detected in human gous mutation in the NDUFS8 gene within another heart, skeletal muscle, and liver (data not shown). In neuropathologically proven Leigh syndrome family.14 comparison with other tissues, the NDUFS7 mRNA content in pancreas, adrenal gland, salivary gland, and Biochemical Analysis of Index Patients stomach seems to be slightly more.
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