Abstract
Golgi apparatus (GA) is a membrane-bound organelle that serves a multitude of critical cellular functions including protein secretion and sorting, and cellular polarity. Many Mendelian diseases are caused by mutations in genes encoding various components of GA. GOLGA2 encodes GM130, a necessary component for the assembly of GA as a single complex, and its deficiency has been found to result in severe cellular phenotypes. We describe the first human patient with a homozygous apparently loss of function mutation in GOLGA2. The phenotype is a neuromuscular disorder characterized by developmental delay, seizures, progressive microcephaly, and muscular dystrophy. Knockdown of golga2 in zebrafish resulted in severe skeletal muscle disorganization and microcephaly recapitulating loss of function human phenotype. Our data suggest an important developmental role of GM130 in humans and zebrafish.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA (2015) Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell reports 10:148–161
Alkuraya FS (2010) Autozygome decoded. Genetics in Medicine 12:765–771
Alkuraya FS (2012) Discovery of rare homozygous mutations from studies of consanguineous pedigrees. Curr Protoc Hum Genet 6.12.1–6.12.13
Alkuraya FS (2013) The application of next-generation sequencing in the autozygosity mapping of human recessive diseases. Hum Genet 132:1197–1211
Alkuraya FS (2014) Genetics and genomic medicine in Saudi Arabia. Mol Genet Genomic Med 2:369–378
Alkuraya FS (2015a) Human knockout research: new horizons and opportunities. Trends Genet 31:108–115
Alkuraya FS (2015b) Primordial dwarfism: an update. Curr Opin Endocrinol Diabetes Obes 22:55–64
Allan VJ, Thompson HM, McNiven MA (2002) Motoring around the Golgi. Nat Cell Biol 4:E236–E242
Alsalem AB, Halees AS, Anazi S, Alshamekh S, Alkuraya FS (2013) Autozygome sequencing expands the horizon of human knockout research and provides novel insights into human phenotypic variation. PLoS Genet 9:e1004030
Barr FA, Nakamura N, Warren G (1998) Mapping the interaction between GRASP65 and GM130, components of a protein complex involved in the stacking of Golgi cisternae. EMBO J 17:3258–3268
Ben-Omran T, Alsulaiman R, Kamel H, Shaheen R, Alkuraya FS (2015) Intrafamilial clinical heterogeneity of CSPP1-related ciliopathy. Am J Med Genet A 167A:2478
Egea G, Serra-Peinado C, Gavilan MP, Rios RM (2015) Cytoskeleton and Golgi-apparatus interactions: a two-way road of function and structure. Cell Health Cytoskeleton 7
Gurel PS, Hatch AL, Higgs HN (2014) Connecting the cytoskeleton to the endoplasmic reticulum and Golgi. Curr Biol 24:R660–R672
Hennet T, Cabalzar J (2015) Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction. Trends Biochem Sci 40:377
Kim S, Hill A, Warman ML, Smits P (2012) Golgi disruption and early embryonic lethality in mice lacking USO1. PLoS One 7:e50530
Lowe M (2011) Structural organization of the Golgi apparatus. Curr Opin Cell Biol 23:85–93
Lowe M, Rabouille C, Nakamura N, Watson R, Jackman M, Jämsä E, Rahman D, Pappin DJ, Warren G (1998) Cdc2 kinase directly phosphorylates the cis-Golgi matrix protein GM130 and is required for Golgi fragmentation in mitosis. Cell 94:783–793
Lowe M, Gonatas NK, Warren G (2000) The mitotic phosphorylation cycle of the cis-Golgi matrix protein GM130. J Cell Biol 149:341–356
Nakamura N, Rabouille C, Watson R, Nilsson T, Hui N, Slusarewicz P, Kreis TE, Warren G (1995) Characterization of a cis-Golgi matrix protein, GM130. J Cell Biol 131:1715–1726
Nakamura N, Lowe M, Levine TP, Rabouille C, Warren G (1997) The vesicle docking protein p115 binds GM130, a cis-Golgi matrix protein, in a mitotically regulated manner. Cell 89:445–455
Potelle S, Klein A, Foulquier F (2015) Golgi post-translational modifications and associated diseases. J Inherit Metab Dis 38:1–11
Santiago-Tirado FH, Bretscher A (2011) Membrane-trafficking sorting hubs: cooperation between PI4P and small GTPases at the trans-Golgi network. Trends Cell Biol 21:515–525
Shaheen R, Faqeih E, Ansari S, Abdel-Salam G, Al-Hassnan ZN, Al-Shidi T, Alomar R, Sogaty S, Alkuraya FS (2014) Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res 24:291–299
Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, ALMoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M (2015) Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med
Shamseldin H, Alazami AM, Manning M, Hashem A, Caluseiu O, Tabarki B, Esplin E, Schelley S, Innes AM, Parboosingh JS (2015) RTTN mutations cause primary microcephaly and primordial Dwarfism in humans. Am J Hum Genet 97:862–868
Smits P, Bolton AD, Funari V, Hong M, Boyden ED, Lu L, Manning DK, Dwyer ND, Moran JL, Prysak M (2010) Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. N Engl J Med 362:206–216
Wei J-H, Zhang ZC, Wynn RM, Seemann J (2015) GM130 Regulates Golgi-Derived Spindle Assembly by Activating TPX2 and Capturing Microtubules. Cell 162:287–299
Yadav S, Puri S, Linstedt AD (2009) A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing. Mol Biol Cell 20:1728–1736
Acknowledgments
We thank the family for their enthusiastic participation. This work was supported in part by King Salman Center for Disability Research (FSA). This work was also supported by King Abdulaziz City for Science and Technology (13-BIO1113-20 to FSA), the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases [K01 AR062601] as well as the Charles H. Hood Foundation Child Health Research Grant to VAG.
Conflict of interest
Authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Hanan E Shamseldin, Alexis H Bennett and Majid Alfadhel have contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
439_2015_1632_MOESM1_ESM.pptx
Figure S1. a RTPCR of GOLGA2 in patient LCL shows no evidence of NMD. b Western blot analysis shows lack of the normal 130 kDa protein in patient LCL compared to the two controls. Figure S2. Golga2 is ubiquitously expressed in adult mouse tissues as shown in this RTPCR experiment using RNA extracted from various mouse tissues including brain and muscle. Supplementary material 1 (PPTX 181 kb)
Rights and permissions
About this article
Cite this article
Shamseldin, H.E., Bennett, A.H., Alfadhel, M. et al. GOLGA2, encoding a master regulator of golgi apparatus, is mutated in a patient with a neuromuscular disorder. Hum Genet 135, 245–251 (2016). https://doi.org/10.1007/s00439-015-1632-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-015-1632-8