New fly model of Meier-Gorlin syndrome

Maxim Balasov, Katarina Akhmetova andIgor Chesnokov. Drosophila model of Meier-Gorlin syndrome based on the mutation in a conserved C-Terminal domain of Orc6. Article first published online: 2 JUL 2015. DOI: 10.1002/ajmg.a.37214

From the abstract: "Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the components of the pre-replicative complex such as Origin Recognition Complex (ORC) subunits Orc1, Orc4, Orc6, and helicase loaders Cdt1 and Cdc6. ... we introduced MGS mutation in Orc6 and established Drosophila model of MGS ..."

Large-scale study of genes on the fly X-chromosome and of rare variants associated with unsolved diseases

Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LE, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ. A Drosophila Genetic Resource of Mutants to Study Mechanisms Underlying Human Genetic Diseases. Cell. 2014 Sep 25;159(1):200-214. PMID: 25259927.

From the abstract: "... We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health."

Hedgehog signaling and cilia--fly study related to a variety of human diseases

Kuzhandaivel A, Schultz SW, Alkhori L, Alenius M. Cilia-Mediated Hedgehog Signaling in Drosophila. Cell Rep. 2014 Apr 23. pii: S2211-1247(14)00249-6. PMID: 24768000.

From the abstract: "Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. ... We demonstrate that several fundamental key aspects of the vertebrate cilia pathway ... are present in Drosophila. ... our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates."

Fruit flies & Cornelia de Lange syndrome. Recent review.

Dorsett D. What fruit flies can tell us about human birth defects. Mo Med. 2013 Jul-Aug;110(4):309-13. PMID: 24003648.

From the abstract: "Here we describe how understanding a gene's function in fruit flies has illuminated the etiology of Cornelia de Lange syndrome."

Hh signaling & disease. Recent review.

Briscoe J, Thérond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013 Jul;14(7):416-29. PMID: 23719536.

Mitochondrial disorders. New fly disease model. Recent report.

Studies in Drosophila contribute to characterization of a human gene newly implicated in disease. Table 2 of the paper presents a comparison of the human disease and fly knockdown phenotypes.

van Bon BW, Oortveld MA, Nijtmans LG, Fenckova M, Nijhof B, Besseling J, Vos M, Kramer JM, de Leeuw N, Castells-Nobau A, Asztalos L, Viragh E, Ruiter M, Hofmann F, Eshuis L, Collavin L, Huynen MA, Asztalos Z, Verstreken P, Rodenburg RJ, Smeitink JA, de Vries BB, Schenck A. CEP89 is required for mitochondrial metabolism and neuronal function in man and fly. Hum Mol Genet. 2013 Apr 10. PMID: 23575228.

Comparison of the glycobiology of humans and flies. Foundational review.

In this recent review, the authors provide a comparison of human and fly glycobiology and describe the "increasing opportunities to dissect pathologic mechanisms using Drosophila genetics."


Katoh T, Tiemeyer M. The N's and O's of Drosophila glycoprotein glycobiology. Glycoconj J. 2012 Aug 31. PubMed PMID: 22936173

The authors indicate that the proteins and pathways discussed are relevant to a number of diseases, including retinitis pigmentosa, Peters Plus syndrome, and diseases "such as autoimmunity, cancer progression, and congenital heart disease, in which altered mucin type O-glycosylation has been implicated." 

Peters Plus syndrome is also known as Krause–van Schooneveld–Kivlin syndrome and Krause–Kivlin syndrome. It is listed on Orphanet and you can read more about it at GeneReviews.

If someone has the time and inclination to pull out the Drosophila gene names mentioned in the paper, and list them as a comment here, please do so.

GWAS implicates ATP1A3 in alternating hemiplegia of childhood.

A genome-wide association study points to mutations in the human gene ATP1A3 as causative in alternating hemiplegia of childhood (AHC). The authors state that distinct mutations in same gene has been implicated in rapid-onset dystonia-parkinsonism.

Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012 Jul 29. doi:10.1038/ng.2358. PubMed PMID: 22842232.

The fly ortholog of ATP1A3 appears to be ATPalpha (FBgn0002921) (DIOPT score = 8, indicating that 8 of 9 published ortholog prediction algorithms/tools predict this human-fly gene relationship).

As annotated in FlyBase, researchers have isolated a large number of mutations in ATPalpha and mutant phenotypes include lethality, the 'bang sensitive' phenotype, hypoactivity, paralysis and neurophysiological defects. Presumably these existing fly models could be used to study AHC.

KANSL1/wah in fly learning and microdeletion syndrome. Breaking Report.

Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41. doi: 10.1038/ng.2262. PubMed PMID: 22544363

Relevant fly gene: waharan (wah) (also called NSL1)


The authors report that RNAi knockdown of wah in mushroom bodies in the fly brain can result in learning defects, providing supporting evidence for a functional link between the conserved KANSL1 gene and brain functions.

At OMIM the syndrome is referred to as autosomal dominant mental retardation-17 (MRD17).


At the cellular level, wah appears to be required for endosomal trafficking.  Read more here:  Lone M, Kungl T, Koper A, Bottenberg W, Kammerer R, Klein M, Sweeney ST, Auburn RP, O'Kane CJ, Prokop A. The nuclear protein Waharan is required for endosomal-lysosomal trafficking in Drosophila. J Cell Sci. 2010 Jul 15;123(Pt 14):2369-74. Epub 2010 Jun 15. PubMed PMID: 20551180; PubMed Central PMCID: PMC2894654.

Microphthalmia. Fly gene knowledge informs disease understanding. Breaking report.

Aldahmesh MA, Mohammed JY, Al-Hazzaa S, Alkuraya FS. Homozygous null mutation in ODZ3 causes microphthalmia in humans. Genet Med. 2012 Jul 5. doi:10.1038/gim.2012.71. PubMed PMID: 22766609.

Relevant genes include:  Ten-m (a.k.a. odz) FBgn0004449