Guy M. Lenk
University of Michigan
TransgeneEndosomeGeneCompound heterozygosityInternal medicineGenetically modified mousePathologyMolecular biologyPhagocytosisRegulation of gene expressionExome sequencingPhosphataseAlleleKinaseGene expression profilingProbandImmunologyAutophagyNeurodegenerationAortic aneurysmPIKFYVEEpilepsyPolymicrogyriaMyelinVacuolizationDiseaseAbdominal aortic aneurysmLysosomeAmyotrophic lateral sclerosisPathogenesisMutationGeneticsBioinformaticsGenetic heterogeneityHaploinsufficiencyCandidate geneMedicineMissense mutationBiologyCell biology
Publications 42
#2Rachel M. Bailey (UTSW: University of Texas Southwestern Medical Center)H-Index: 1
Last. Cathleen M. LutzH-Index: 27
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Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten lifespan. There is currently no treatment for CMT4J. Here we present th...
#1Guy M. Lenk (UM: University of Michigan)H-Index: 23
#2Paymaan Jafar-NejadH-Index: 17
Last. Miriam H. MeislerH-Index: 66
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OBJECTIVE: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mous...
12 CitationsSource
#1Guy M. Lenk (UM: University of Michigan)H-Index: 23
#2Young Nam Park (UM: University of Michigan)H-Index: 5
Last. Jacob O. Kitzman (UM: University of Michigan)H-Index: 36
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Defective biosynthesis of the phospholipid PI(3,5)P2 underlies neurological disorders characterized by cytoplasmic accumulation of large lysosome-derived vacuoles. To identify novel genetic causes of lysosomal vacuolization, we developed an assay for enlargement of the lysosome compartment that is amenable to cell sorting and pooled screens. We first demonstrated that the enlarged vacuoles that accumulate in fibroblasts lacking FIG4, a PI(3,5)P2 biosynthetic factor, have a hyperacidic pH compare...
7 CitationsSource
#1Claudio M. de Gusmao (Boston Children's Hospital)H-Index: 6
#2Scellig S. D. Stone (Boston Children's Hospital)H-Index: 14
Last. Lance H. Rodan (Boston Children's Hospital)H-Index: 21
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2 CitationsSource
#1Guy M. Lenk (UM: University of Michigan)H-Index: 23
#2Ian R. Berry (Leeds Teaching Hospitals NHS Trust)H-Index: 9
Last. Miriam H. Meisler (Leeds Teaching Hospitals NHS Trust)H-Index: 66
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The lipid phosphatase gene FIG4 is responsible for Yunis-Varon syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cult...
6 CitationsSource
#1Christin BissigH-Index: 4
#2Pauline CroiséH-Index: 6
Last. Guillaume van NielH-Index: 31
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There was an error in J. Cell Sci. (2019) 132, [jcs229500][1] ([doi:10.1242/jcs.229500][2]). The DMSO lanes in [Fig. 2][3]C and D were duplicated in [Fig. 2][3]E and F, respectively, which contravenes our image presentation guidelines. The authors supplied full blots for all these panels and
1 CitationsSource
#1Christin Bissig (CNRS: Centre national de la recherche scientifique)H-Index: 4
#2Pauline Croisé (Paris V: Paris Descartes University)H-Index: 6
Last. Guillaume van Niel (Paris V: Paris Descartes University)H-Index: 31
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ABSTRACT The metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex, mutations in which are associated with hypopigmentation in mice. These pigmentation defects indicate a key, but as yet unexplored, physiological relevance of this complex in the biogenesis of melanosomes. Here, we show that PIKfyve activity regulates formation of amyloid matrix composed of PMEL protein within the early endosomes in melanocytes, called stage I melanosomes. PIKfyve activity controls the membr...
11 CitationsSource
#1Yevgeniya A. Mironova (UM: University of Michigan)H-Index: 11
#2Jing-Ping Lin (UM: University of Michigan)H-Index: 4
Last. Roman J GigerH-Index: 5
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: The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varon syndrome. Constitutive Fig4-/- mice exhibit intention tremo...
8 CitationsSource
#1Christopher H. Choy (RyeU: Ryerson University)H-Index: 6
#2Golam Saffi (RyeU: Ryerson University)H-Index: 2
Last. Roberto J. Botelho (RyeU: Ryerson University)H-Index: 27
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Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux, and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects including embryonic le...
53 CitationsSource
#1Jennifer NischanH-Index: 2
#2Zoran GatalicaH-Index: 62
Last. Helena KuivaniemiH-Index: 74
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