Oláhová M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Frésard L, Waggott D, Zink EM, Kim YM, Heyman HM, Stratton KG, Webb-Robertson BM; Undiagnosed Diseases Network, Snyder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller DM, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wangler MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT. Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 2018 Feb 16. pii: S0002-9297(18)30042-9. PMID: 29478781.
From the abstract: "... Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. ... Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation."
Wednesday, February 28, 2018
Friday, February 16, 2018
Review discusses re-think of pathogenesis underlying Ehlers-Danlos syndrome based on results of fly study
Xiao G, Zhou B. ZIP13: A Study of Drosophila Offers an Alternative Explanation for the Corresponding Human Disease. Front Genet. 2018 Jan 31;8:234. PMID: 29445391; PubMed Central PMCID: PMC5797780.
The abstract: "The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. Previously we identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is in fact physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD-EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Altogether three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties."
The abstract: "The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. Previously we identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is in fact physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD-EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Altogether three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties."
Tuesday, February 6, 2018
Drosophila experiments help inform study of Menkes disease
Zlatic SA, Vrailas-Mortimer A, Gokhale A, Carey LJ, Scott E, Burch R, McCall MM, Rudin-Rush S, Davis JB, Hartwig C, Werner E, Li L, Petris M, Faundez V. Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees. Cell Syst. 2018 Jan 30. pii: S2405-4712(18)30008-5. PMID: 29397366.
From the abstract: "Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. ... We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes."
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