Whole Exome Sequencing Identifies Two Novel Mutations in the Reticulon 4–Interacting Protein 1 Gene in a Chinese Family with Autosomal Recessive Optic Neuropathies
Autosomal recessive optic neuropathies (IONs) are extremely rare disorders affecting retinal ganglion cells and the nervous system. RTN4IP1 has recently been identified as the third known gene associated with the autosomal recessive ION optic atrophy 10 (OPA10). Patients with RTN4IP1 mutations show early-onset optic neuropathy that can be followed by additional neurological symptoms such as seizures, ataxia, mental retardation, or even severe encephalopathy. Here, we report two siblings from a Chinese family who presented with early-onset optic neuropathy, epilepsy, and mild intellectual disability. Using whole exome sequencing combined with Sanger sequencing, we identified novel compound heterozygous RTN4IP1 mutations (c.646G > A, p.G216R and c.1162C > T, p.R388X) which both co-segregated with the disease phenotype and were predicted to be disease-causing by prediction software. An in vitro functional study in urine cells obtained from one of the patients revealed low expression of the RTN4IP1 protein. Our results identify novel compound heterozygous mutations in RTN4IP1 which are associated with OPA10, highlighting the frequency of RTN4IP1 mutations in human autosomal recessive IONs. To our knowledge, this is the first report of RTN4IP1 carriers from China.
KeywordsInherited optic neuropathies OPA10 RTN4IP1 Optic atrophy Epilepsy
We thank Sarah Williams, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn), for editing the English text of a draft of this manuscript.
This work was supported by the National Natural Science Foundation of China (grant nos. 81701133, 81322017, 81771230, and U1505222), the Joint Funds for the Innovation of Science and Technology, Fujian Province (2017Y9087), and the National Key Clinical Specialty Discipline Construction Program and Key Clinical Specialty Discipline Construction Program of Fujian.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from the parents of the children.
- Angebault C, Guichet PO, Talmat-Amar Y, Charif M, Gerber S, Fares-Taie L, Gueguen N, Halloy F, Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Megy C, Teigell M, Delettre C, Rossel M, Meunier I, Preising M, Lorenz B, Carelli V, Chinnery PF, Yu-Wai-Man P, Kaplan J, Roubertie A, Barakat A, Bonneau D, Reynier P, Rozet JM, Bomont P, Hamel CP, Lenaers G (2015) Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies. Am J Hum Genet 97(5):754–760PubMedPubMedCentralCrossRefGoogle Scholar
- Charif M, Nasca A, Thompson K, Gerber S, Makowski C, Mazaheri N, Bris C, Goudenege D, Legati A, Maroofian R, Shariati G, Lamantea E, Hopton S, Ardissone A, Moroni I, Giannotta M, Siegel C, Strom TM, Prokisch H, Vignal-Clermont C, Derrien S, Zanlonghi X, Kaplan J, Hamel CP, Leruez S, Procaccio V, Bonneau D, Reynier P, White FE, Hardy SA, Barbosa IA, Simpson MA, Vara R, Perdomo Trujillo Y, Galehdari H, Deshpande C, Haack TB, Rozet JM, Taylor RW, Ghezzi D, Amati-Bonneau P, Lenaers G (2018) Neurologic phenotypes associated with mutations in RTN4IP1 (OPA10) in children and young adults. JAMA Neurol 75(1):105–113PubMedCrossRefGoogle Scholar
- Hanein S, Perrault I, Roche O, Gerber S, Khadom N, Rio M, Boddaert N, Jean-Pierre M, Brahimi N, Serre V, Chretien D, Delphin N, Fares-Taie L, Lachheb S, Rotig A, Meire F, Munnich A, Dufier JL, Kaplan J, Rozet JM (2009) TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy. Am J Hum Genet 84(4):493–498PubMedPubMedCentralCrossRefGoogle Scholar
- Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, Stenzel W, Graf R, van den Heuvel L, Ropers HH, Wienker TF, Hubner C, Langer T, Kaindl AM (2016) Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. eLife,5,(2016-07-28), 2016, 5.Google Scholar
- Jurkute N, Majander A, Bowman R, Votruba M, Abbs S, Acheson J, Lenaers G, Amati-Bonneau P, Moosajee M, Arno G, Yu-Wai-Man P (2019) Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches. Eur J Hum Genet 27(3):494-502PubMedCrossRefGoogle Scholar
- Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C (2014) Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet 51(12):834–838PubMedCrossRefGoogle Scholar
- Spiegel R, Pines O, Ta-Shma A, Burak E, Shaag A, Halvardson J, Edvardson S, Mahajna M, Zenvirt S, Saada A, Shalev S, Feuk L, Elpeleg O (2012) Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet 90(3):518–523PubMedPubMedCentralCrossRefGoogle Scholar