Biallelic variants in AGMO with diminished enzyme activity are associated with a neurodevelopmental disorder
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Alkylglycerol monooxygenase (AGMO) is the only enzyme known to cleave the O-alkyl bonds of ether lipids (alkylglycerols) which are essential components of cell membranes. A homozygous frameshift variant [p.(Glu324LysfsTer12)] in AGMO has recently been reported in two male siblings with syndromic microcephaly. In this study, we identified rare nonsense, in frame deletion, and missense biallelic variants in AGMO in two unrelated individuals with neurodevelopmental disabilities. We assessed the activity of seven disease associated AGMO variants including the four variants identified in our two affected individuals expressed in human embryonic kidney (HEK293T) cells. We demonstrated significantly diminished enzyme activity for all disease-associated variants, supporting the mechanism as decreased AGMO activity. Future mechanistic studies are necessary to understand how decreased AGMO activity leads to the neurologic manifestations.
We thank the families for their generous contribution, and Petra Loitzl, Nina Madl, and Rita Holzknecht for expert technical assistance. This work was supported by Grants from Austrian Science Fund (fwf) projects to Katrin Watschinger (P30800) and Ernst R. Werner (P28769), and the SFARI and the JPB Foundation to Wendy K. Chung.
VO analyzed the data, drafted and critically reviewed the manuscript. KW analyzed the data, drafted and critically reviewed the manuscript. DN provided with the clinical data, critically reviewed the manuscript. JM provided with the clinical data, critically reviewed the manuscript. DB provided with the clinical data, critically reviewed the manuscript. MH analyzed the data and critically reviewed the manuscript. ERW conceived of the study, analyzed the data, drafted, and critically reviewed the manuscript. WKC conceived of the study, analyzed the data, drafted and critically reviewed the manuscript.
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Conflict of Interest
The authors declare no competing interests related to presented study.
- Alrayes N, Mohamoud HS, Ahmed S, Almramhi MM, Shuaib TM, Wang J, Al-Aama JY, Everett K, Nasir J, Jelani M (2016) The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family. J Neurol Sci 363:240–244. https://doi.org/10.1016/j.jns.2016.02.063 CrossRefPubMedGoogle Scholar
- Keller MA, Zander U, Fuchs JE, Kreutz C, Watschinger K, Mueller T, Golderer G, Liedl KR, Ralser M, Krautler B, Werner ER, Marquez JA (2014) A gatekeeper helix determines the substrate specificity of Sjogren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase. Nat Commun 5:4439. https://doi.org/10.1038/ncomms5439
- Marquet S, Bucheton B, Reymond C, Argiro L, El-Safi SH, Kheir MM, Desvignes JP, Beroud C, Mergani A, Hammad A, Dessein AJ (2017) Exome sequencing identifies two variants of the alkylglycerol monooxygenase gene as a cause of relapses in visceral leishmaniasis in children, in Sudan. J Infect Dis 216:22–28. https://doi.org/10.1093/infdis/jix277 CrossRefPubMedGoogle Scholar
- Watschinger K, Keller MA, Golderer G, Hermann M, Maglione M, Sarg B, Lindner HH, Hermetter A, Werner-Felmayer G, Konrat R, Hulo N, Werner ER (2010) Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes. Proc Natl Acad Sci USA 107:13672–13677. https://doi.org/10.1073/pnas.1002404107 CrossRefPubMedGoogle Scholar
- Watschinger K, Fuchs JE, Yarov-Yarovoy V, Keller MA, Golderer G, Hermetter A, Werner-Felmayer G, Hulo N, Werner ER (2012) Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase. Biochem J 443:279–286. https://doi.org/10.1042/bj20111509 CrossRefPubMedPubMedCentralGoogle Scholar
- Watschinger K, Keller MA, McNeill E, Alam MT, Lai S, Sailer S, Rauch V, Patel J, Hermetter A, Golderer G, Geley S, Werner-Felmayer G, Plumb RS, Astarita G, Ralser M, Channon KM, Werner ER (2015) Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome. Proc Natl Acad Sci USA 112:2431–2436. https://doi.org/10.1073/pnas.1414887112 CrossRefPubMedGoogle Scholar