The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping

American Journal of Human Genetics

Volumn 104, Issue 4, 2019, Pages 749-757

  Marbach, Felix ^a,b   Rustad, Cecilie F ^c   Riess, Angelika ^d   Đukić, Dejan ^e   Hsieh, Tzung Chien ^f   Jobani, Itamar ^g   Prescott, Trine ^h   Bevot, Andrea ⁱ   Erger, Florian ^a,b   Houge, Gunnar ^j,k   Redfors, Maria ^l,m   Altmueller, Janine ⁿ   Stokowy, Tomasz ^k   Gilissen, Christian ^o   Kubisch, Christian ^p   Scarano, Emanuela ^q   Mazzanti, Laura ^q   Fiskerstrand, Torunn ^j,k   Krawitz, Peter M ^f   Lessel, Davor ^p   Netzer, Christian ^a,b   more..

^a UNIVERSITY OF COLOGNE   (Germany)

^b UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^c OSLO UNIVERSITY HOSPITAL   (Norway)

^d UNIVERSITY OF TÜBINGEN   (Germany)

^e GREGOR MENDEL INSTITUTE OF MOLECULAR PLANT BIOLOGY   (Austria)

^f UNIVERSITY HOSPITAL BONN   (Germany)

^g Private contributor   (Israel)

^h TELEMARK HOSPITAL   (Norway)

ⁱ UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

^j HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^k UNIVERSITY OF BERGEN   (Norway)

^l UNIVERSITY OF OSLO   (Norway)

^m LOVISENBERG DIAKONALE HOSPITAL   (Norway)

ⁿ UNIVERSITY OF COLOGNE   (Germany)

^o RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^p UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^q UNIVERSITY OF BOLOGNA   (Italy)

more..

Author keywords

LEM domain containing protein 2 ; deep neuronal network and intra syndromal similarity; next generation phenotyping ; nuclear envelopathy ; progeria like

Indexed keywords

ENVELOPE PROTEIN; LEM DOMAIN CONTAINING PROTEIN 2; UNCLASSIFIED DRUG; LEMD2 PROTEIN, HUMAN; MEMBRANE PROTEIN; NUCLEAR PROTEIN;

AGE; ALGORITHM; ARTICLE; ARTIFICIAL INTELLIGENCE; ARTIFICIAL NEURAL NETWORK; CASE REPORT; CELL NUCLEUS MEMBRANE; CHILD; CLINICAL ARTICLE; COMPUTER ANALYSIS; ENVELOPE GENE; ETHNICITY; FACE; FACIES; FIBROBLAST; GENE MUTATION; GENETIC DISORDER; GROWTH RETARDATION; HUMAN; IMMUNOFLUORESCENCE; JAW MALFORMATION; LEMD2 GENE; NUCLEAR ENVELOPATHY; NUCLEAR LAMINA; PHENOTYPE; PRESCHOOL CHILD; PRIORITY JOURNAL; PROGERIA; PROTEIN LOCALIZATION; SCHOOL CHILD; TREMOR; ADOLESCENT; CELL NUCLEUS; COMPUTER ASSISTED DIAGNOSIS; GENETICS; MALE; MASS SCREENING; MEDICAL INFORMATICS; METABOLISM; MUTATION; PROCEDURES; PROGNOSIS; SYNDROME; TUMOR CELL LINE;

ADOLESCENT; ARTIFICIAL INTELLIGENCE; CELL LINE, TUMOR; CELL NUCLEUS; CHILD; CHILD, PRESCHOOL; DIAGNOSIS, COMPUTER-ASSISTED; FACE; FIBROBLASTS; HUMANS; MALE; MASS SCREENING; MEDICAL INFORMATICS; MEMBRANE PROTEINS; MUTATION; NUCLEAR PROTEINS; PHENOTYPE; PROGERIA; PROGNOSIS; SYNDROME;

EID: 85063638412     PISSN: 00029297     EISSN: 15376605     Source Type: Journal    
DOI: 10.1016/j.ajhg.2019.02.021     Document Type: Article

References (27)

1. Somech, R., Shaklai, S., Amariglio, N., Rechavi, G., Simon, A.J., Nuclear envelopathies—raising the nuclear veil. Pediatr. Res. 57 (2005), 8R–15R.
2. Merideth, M.A., Gordon, L.B., Clauss, S., Sachdev, V., Smith, A.C., Perry, M.B., Brewer, C.C., Zalewski, C., Kim, H.J., Solomon, B., et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N. Engl. J. Med. 358 (2008), 592–604.
3. Davidson, P.M., Lammerding, J., Broken nuclei—lamins, nuclear mechanics, and disease. Trends Cell Biol. 24 (2014), 247–256.
4. Cabanillas, R., Cadiñanos, J., Villameytide, J.A., Pérez, M., Longo, J., Richard, J.M., Alvarez, R., Durán, N.S., Illán, R., González, D.J., López-Otín, C., Néstor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am. J. Med. Genet. A. 155A (2011), 2617–2625.
5. Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P.C., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S.J., et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat. Genet. 36 (2004), 1213–1218.
6. Brachner, A., Reipert, S., Foisner, R., Gotzmann, J., LEM2 is a novel MAN1-related inner nuclear membrane protein associated with A-type lamins. J. Cell Sci. 118 (2005), 5797–5810.
7. Barrales, R.R., Braun, S., Chromatin binding and silencing: Two roles of the same protein Lem2. Microb. Cell 3 (2016), 185–188.
8. Thanisch, K., Song, C., Engelkamp, D., Koch, J., Wang, A., Hallberg, E., Foisner, R., Leonhardt, H., Stewart, C.L., Joffe, B., Solovei, I., Nuclear envelope localization of LEMD2 is developmentally dynamic and lamin A/C dependent yet insufficient for heterochromatin tethering. Differentiation 94 (2017), 58–70.
9. Boone, P.M., Yuan, B., Gu, S., Ma, Z., Gambin, T., Gonzaga-Jauregui, C., Jain, M., Murdock, T.J., White, J.J., Jhangiani, S.N., et al. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death. Mol. Genet. Genomic Med. 4 (2015), 77–94.
10. Dimopoulou, A., Fischer, B., Gardeitchik, T., Schröter, P., Kayserili, H., Schlack, C., Li, Y., Brum, J.M., Barisic, I., Castori, M., et al. Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Mol. Genet. Metab. 110 (2013), 352–361.
11. Lessel, D., Ozel, A.B., Campbell, S.E., Saadi, A., Arlt, M.F., McSweeney, K.M., Plaiasu, V., Szakszon, K., Szőllős, A., Rusu, C., et al. Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Hum. Genet. 137 (2018), 921–939.
12. Sobreira, N., Schiettecatte, F., Boehm, C., Valle, D., Hamosh, A., New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene. Hum. Mutat. 36 (2015), 425–431.
13. Conrad, D.F., Keebler, J.E., DePristo, M.A., Lindsay, S.J., Zhang, Y., Casals, F., Idaghdour, Y., Hartl, C.L., Torroja, C., Garimella, K.V., et al., 1000 Genomes Project. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43 (2011), 712–714.
14. Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks, E., Fennell, T., O'Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B., et al., Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536 (2016), 285–291.
15. Ulbert, S., Antonin, W., Platani, M., Mattaj, I.W., The inner nuclear membrane protein Lem2 is critical for normal nuclear envelope morphology. FEBS Lett. 580 (2006), 6435–6441.
16. Huber, M.D., Guan, T., Gerace, L., Overlapping functions of nuclear envelope proteins NET25 (Lem2) and emerin in regulation of extracellular signal-regulated kinase signaling in myoblast differentiation. Mol. Cell. Biol. 29 (2009), 5718–5728.
17. Eriksson, M., Brown, W.T., Gordon, L.B., Glynn, M.W., Singer, J., Scott, L., Erdos, M.R., Robbins, C.M., Moses, T.Y., Berglund, P., et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423 (2003), 293–298.
18. Vigouroux, C., Auclair, M., Dubosclard, E., Pouchelet, M., Capeau, J., Courvalin, J.C., Buendia, B., Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene. J. Cell Sci. 114 (2001), 4459–4468.
19. Gurovich, Y., Hanani, Y., Bar, O., Nadav, G., Fleischer, N., Gelbman, D., Basel-Salmon, L., Krawitz, P.M., Kamphausen, S.B., Zenker, M., et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat. Med. 25 (2019), 60–64.
20. Schroff, F., Kalenichenko, D., Philbin, J., FaceNet: A Unified Embedding for Face Recognition and Clustering. arXiv, 2015 arXiv:1503.03832 https://arxiv.org/abs/1503.03832.
21. Gu, M., LaJoie, D., Chen, O.S., von Appen, A., Ladinsky, M.S., Redd, M.J., Nikolova, L., Bjorkman, P.J., Sundquist, W.I., Ullman, K.S., Frost, A., LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. Proc. Natl. Acad. Sci. USA 114 (2017), E2166–E2175.
22. Barrales, R.R., Forn, M., Georgescu, P.R., Sarkadi, Z., Braun, S., Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2. Genes Dev. 30 (2016), 133–148.
23. Xu, Y.J., Inner nuclear membrane protein Lem2 facilitates Rad3-mediated checkpoint signaling under replication stress induced by nucleotide depletion in fission yeast. Cell. Signal. 28 (2016), 235–245.
24. Tapia, O., Fong, L.G., Huber, M.D., Young, S.G., Gerace, L., Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases. PLoS ONE, 10, 2015, e0116196.
25. Dudding-Byth, T., Baxter, A., Holliday, E.G., Hackett, A., O'Donnell, S., White, S.M., Attia, J., Brunner, H., de Vries, B., Koolen, D., et al. Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability. BMC Biotechnol., 17, 2017, 90.
26. Ferry, Q., Steinberg, J., Webber, C., FitzPatrick, D.R., Ponting, C.P., Zisserman, A., Nellåker, C., Diagnostically relevant facial gestalt information from ordinary photos. eLife, 3, 2014, e02020.
27. Brunner, H.G., van Driel, M.A., From syndrome families to functional genomics. Nat. Rev. Genet. 5 (2004), 545–551.