LETM1, a gene deleted in Wolf–Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein

Schlickum, Stephanie; Moghekar, Abhay; Simpson, Jeremy C.; Steglich, Cordula; O’Brien, Richard; Winterpacht, Andreas; Endele, Sabine

doi:10.1016/j.ygeno.2003.08.013

Cited by 95 publications

(77 citation statements)

References 21 publications

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“…Deletion of YOL027 has been shown to cause changes in mitochondrial morphology and suggested a mitochondrial location of the YOL027 gene product (29). A recent report involving GFPtagged versions of LetM1p (30), as well as this study on human LetM1p, yeast Yol027p, and yeast Ypr125p, confirm a mitochondrial location of LetM1p and its yeast homologs.…”

Section: Discussionsupporting

confidence: 69%

The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

Nowikovsky

Froschauer

Zsurka

et al. 2004

Journal of Biological Chemistry

176

247

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Respiring mitochondria maintain a membrane potential (⌬⌿) 1 of Ϫ150 to Ϫ180 mV (⌬⌿, inside negative). This high ⌬⌿ constitutes a large driving force for the electrophoretic influx of cations, either through specific channels or by diffusion through the membrane. Several cation channels have been characterized physiologically (reviewed in Refs. 1 and 2), and recently, a single one has been identified molecularly (3). These transport systems seem to have intrinsic control mechanisms which ensure that the matrix cation concentrations stay within physiological ranges, far below chemical equilibrium.Diffusive permeability of the inner mitochondrial membrane to ions is generally low but physiologically significant, as it lowers the pH gradient and membrane potential. Moreover, if not counteracted by extrusion, steadily increasing concentrations of matrix cations (and of compensating anions) will lead to an imbalance of osmotic pressure across the inner mitochondrial membrane. As a consequence, water will pass through the membrane, causing excessive swelling and eventual rupture of the organelle (1, 2, 4).As first proposed by P. Mitchell (5), mitochondria have carrier systems allowing the electroneutral exchange of cations against H ϩ (and anions against OH Ϫ ). These exchangers counteract the ⌬⌿-driven cation leakage of the membrane and also cation imbalances due to changes in mitochondrial physiology. Mitochondrial cation distribution is, therefore, a steady state, in which the accumulation ratio is modulated by the relative rates of cation influx and efflux by means of separate pathways.Many physiological studies have been devoted to cation/H ϩ exchange systems (reviewed in Ref.

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Section: Discussionsupporting

confidence: 69%

The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

Nowikovsky

Froschauer

Zsurka

et al. 2004

Journal of Biological Chemistry

176

247

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“…LETM1 encodes a ubiquitously expressed leucine zipper-EF-handcontaining transmembrane 1 protein 18 with intracellular localization to mitochondria 36,37 and the ER. 38 Its cellular function as an ion exchanger [37][38][39][40][41] suggests potential roles in cell signaling and energy production.…”

Section: Discussionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

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Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

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“…Letm1 (leucine zipper EF hand-containing transmembrane protein 1) is evolutionarily conserved in diverse eukaryotic lineages bearing energized mitochondria, ranging from opisthokonts, comprising metazoa and fungi, to plastid-containing plants and apicomplexans (1,2). Letm1, a protein predicted to be embedded into the mitochondrial (mt) 4 inner membrane (IM) via a predicted transmembrane domain (1,3,4), came into prominence because its gene locus is often within a deletion, occurring to different extents, on the short arm of human chromosome 4, causing Wolf-Hirschhorn syndrome (5).…”

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confidence: 99%

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

Hashimi

McDonald

Stříbrná

et al. 2013

Journal of Biological Chemistry

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Background: Letm1 is a mitochondrial protein attributed disparate roles, including cation/proton antiport and translation. Results: Letm1 RNAi silencing in Trypanosoma brucei triggers swelling mitochondria and translation arrest that is ameliorated by chemical potassium/proton exchangers. Conclusion:The ancestral function of Letm1, to maintain mitochondrial potassium homeostasis, shows remarkable conservation. Significance: Results from diverged T. brucei provide a better understanding of Letm1 function throughout eukaryotes.

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LETM1, a gene deleted in Wolf–Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein

Cited by 95 publications

References 21 publications

The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis

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