Cerebral hypomyelination associated with biallelic variants of FIG4

Published on May 1, 2019in Human Mutation4.124
· DOI :10.1002/HUMU.23720
Guy M. Lenk23
Estimated H-index: 23
(UM: University of Michigan),
Ian R. Berry9
Estimated H-index: 9
(Leeds Teaching Hospitals NHS Trust)
+ 20 AuthorsMiriam H. Meisler66
Estimated H-index: 66
(Leeds Teaching Hospitals NHS Trust)
Sources
Abstract
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. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
📖 Papers frequently viewed together
103 Citations
16 Citations
References36
Newest
#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
view all 8 authors...
: 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
#1Zachary N Wilson (CU: University of Colorado Boulder)H-Index: 1
#2Amber L. Scott (CU: University of Colorado Boulder)H-Index: 2
Last. Greg Odorizzi (CU: University of Colorado Boulder)H-Index: 27
view all 4 authors...
: Lysosomes are dynamic organelles with critical roles in cellular physiology. The lysosomal signaling lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is a key regulator that has been implicated to control lysosome ion homeostasis, but the scope of ion transporters targeted by PI(3,5)P2 and the purpose of this regulation is not well understood. Through an unbiased screen in Saccharomyces cerevisiae, we identified loss-of-function mutations in the vacuolar H+-ATPase (V-ATPase) and in Vnx1...
10 CitationsSource
#1Sonja A. Kirsch (FAU: University of Erlangen-Nuremberg)H-Index: 7
#2Andreas Kugemann (FAU: University of Erlangen-Nuremberg)H-Index: 1
Last. Petra Dietrich (FAU: University of Erlangen-Nuremberg)H-Index: 29
view all 5 authors...
Mammalian two-pore channels (TPCs) are activated by the low-abundance membrane lipid phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) present in the endo-lysosomal system. Malfunction of human TPC1 or TPC2 (hTPC) results in severe organellar storage diseases and membrane trafficking defects. Here, we compared the lipid-binding characteristics of hTPC2 and of the PI(3,5)P2-insensitive TPC1 from the model plant Arabidopsis thaliana. Combination of simulations with functional analysis of channel mutants...
10 CitationsSource
#1Ji She (UTSW: University of Texas Southwestern Medical Center)H-Index: 10
#2Jiangtao Guo (ZJU: Zhejiang University)H-Index: 13
Last. Xiao Chen Bai (UTSW: University of Texas Southwestern Medical Center)H-Index: 37
view all 6 authors...
Two-pore channels (TPCs) are organellar voltage-dependent ion channels that are widely expressed in both animals and plants. In mammals, TPC1 and TPC2 regulate the physiological functions of the endolysosomal system. Here, Youxing Jiang and colleagues report the structure of mouse TPC1, a sodium ion (Na+)-selective channel, in both its apo closed state and phospholipid-bound open state by cryo-electron microscopy. Along with functional studies, these data underlie the basis for the difference in...
72 CitationsSource
#1Chloe A StutterdH-Index: 6
#2Peter Diakumis (WEHI: Walter and Eliza Hall Institute of Medical Research)H-Index: 5
Last. Paul J. Lockhart (University of Melbourne)H-Index: 47
view all 12 authors...
Objective To characterize the clinical features and neuropathology associated with recessive VAC14 mutations. Methods Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination. Results We identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, ...
9 CitationsSource
#1Marjo S. van der Knaap (VU: VU University Amsterdam)H-Index: 76
#2Marianna Bugiani (VU: VU University Amsterdam)H-Index: 14
Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed...
112 CitationsSource
#1Lukmanee Tradtrantip (UCSF: University of California, San Francisco)H-Index: 21
#2Xiaoming Yao (UCSF: University of California, San Francisco)H-Index: 13
Last. Alan S. Verkman (UCSF: University of California, San Francisco)H-Index: 166
view all 5 authors...
Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement ‘bystander mechanism’ to account for early o...
19 CitationsSource
#1Jessica M. Mc Donald (NU: Northwestern University)H-Index: 10
#2Dimitri KraincH-Index: 59
Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease...
15 CitationsSource
#1Sietske H. Kevelam (VU: VU University Amsterdam)H-Index: 9
#2Marjan E. Steenweg (VU: VU University Amsterdam)H-Index: 12
Last. Marjo S. van der Knaap (VU: VU University Amsterdam)H-Index: 76
view all 10 authors...
Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were u...
51 CitationsSource
#1Monkol Lek (Harvard University)H-Index: 50
#2Konrad J. Karczewski (Harvard University)H-Index: 45
Last. Daniel G. MacArthur (Broad Institute)H-Index: 80
view all 79 authors...
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence fo...
6,563 CitationsSource
Cited By6
Newest
#1Wandong Bao (SWU: Southwest University)
#2Xinjuan Wang (SWU: Southwest University)
Last. Rui Ni (SWU: Southwest University)
view all 4 authors...
The phospholipid phosphatase FIG4/Fig4 is a subunit of PIKFYVE/Pikfyve kinase complex that synthesizes phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a key regulator of endolysosomal trafficking and function. Loss of FIG4/Fig4 leads to intracellular deficiency of PI(3,5)P2 signaling and multiple endolysosomal defects. Previous works were focused on the effects of FIG4/Fig4 mutations in the nervous and musculoskeletal systems in human clinical and animal studies. In this study, we describe a ...
Source
#1Raju V. S. Rajala (OU: University of Oklahoma)H-Index: 28
The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (PIs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind phosphoinositides and are recruited to cell membranes. Through the activities of PI kinases and PI phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule phosphatidylinositol. PI signals regulate a wide r...
4 CitationsSource
#1Georgia C. Wright (University of Cambridge)H-Index: 1
#2Richard BrownH-Index: 4
Last. Pooja D. Harijan (University of Cambridge)H-Index: 1
view all 12 authors...
Variants in the FIG4 gene which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Biallelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4 J (CMT4J) and Yunis-Varon syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A ...
1 CitationsSource
#1Milan Zimmermann (University of Tübingen)H-Index: 7
#1Milan Zimmermann (German Center for Neurodegenerative Diseases)H-Index: 1
Last. Ludger Schöls (German Center for Neurodegenerative Diseases)H-Index: 77
view all 11 authors...
Abstract Background Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varon syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. Objectives To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. Methods Phenotyping of five new patients with FIG4-related disease. W...
3 CitationsSource
#1Gholson J. LyonH-Index: 42
#2Elaine MarchiH-Index: 4
Last. Milen VelinovH-Index: 18
view all 15 authors...
: Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a disti...
4 CitationsSource
#1Assia Shisheva (WSU: Wayne State University)H-Index: 33
#2Diego Sbrissa (WSU: Wayne State University)H-Index: 26
Last. Jun Li (WSU: Wayne State University)H-Index: 101
view all 4 authors...
Charcot-Marie-Tooth disease type-4J (CMT4J), an autosomal recessively inherited peripheral neuropathy characterized by neuronal degeneration, segmental demyelination, and limb muscle weakness, is caused by compound heterozygous mutations in the SAC3/FIG4 gene, resulting in SAC3/FIG4 protein deficiency. SAC3/FIG4 is a phosphatase that not only turns over PtdIns(3,5)P2 to PtdIns3P but also promotes PtdIns(3,5)P2 synthesis by activating the PIKFYVE kinase that also makes PtdIns5P. Whether CMT4J pat...
5 CitationsSource