Alternative titles; symbols
HGNC Approved Gene Symbol: DNM1L
Cytogenetic location: 12p11.21 Genomic coordinates (GRCh38): 12:32,679,301-32,745,650 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.21 | Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 | 614388 | Autosomal dominant; Autosomal recessive | 3 |
| Optic atrophy 5 | 610708 | Autosomal dominant | 3 |
DNM1L belongs to the dynamin (see DNM1; 602377) family of large GTPases that mediate membrane remodeling during a variety of cellular processes. DNM1L has an important role in the fission of mitochondria and peroxisomes (summary by Pitts et al. (2004)).
By PCR amplification of human hepatoma HepG2 cDNA using oligonucleotides based on human ESTs homologous to Vps1 and Dnm1 (602377), Shin et al. (1997) obtained a partial cDNA which they used to screen a HepG2 cDNA library. They isolated cDNAs encoding a predicted 736-amino acid protein, DNM1L, which they designated DVLP. DVLP contains the highly conserved N-terminal tripartite GTP-binding domain, but it lacks the pleckstrin homology domain and proline-rich region. It shares 45% and 42% amino acid identity with yeast Dnm1 and Vps1, respectively. Immunofluorescence studies of mammalian cells showed that DVLP localized to the perinuclear region and did not colocalize with endoplasmic reticulum (ER) or Golgi marker proteins.
By searching an EST database with a rat dynamin-3 (see 611445) amino acid sequence, Imoto et al. (1998) identified a human cDNA encoding DNM1L, which they called DRP1. Northern blot analysis indicated that DRP1 was expressed ubiquitously in human tissues, with highest levels in skeletal muscle, heart, kidney, and brain. Immunolocalization studies showed that DRP1 was enriched in a perinuclear compartment that labeled with ER and Golgi markers. The localization of DRP1 was highly similar to the localization of the ER and cis-Golgi GTPase RAB1 (179508), but not to the localization of the trans-Golgi GTPase RAB6 (179513).
By immunoscreening a HeLa cell cDNA expression library with serum from a scleroderma (181750) patient, Kamimoto et al. (1998) isolated cDNAs encoding DNM1L, which they referred to as DYMPLE. They identified cDNAs corresponding to 3 alternatively spliced DYMPLE transcripts, which encode a deduced 736-amino acid protein and deduced isoforms containing a 29- or 37-amino acid deletion in the C-terminal region. RT-PCR analysis of mouse tissues demonstrated that alternative splicing occurred in a tissue-specific manner. Northern blot analysis detected 2.5- and 4.2-kb DYMPLE transcripts in all human tissues examined. The authors reported that these transcripts were alternatively polyadenylated. In situ hybridization analysis of mouse brain showed abundant expression of Dymple mRNA in the cerebellum and in several regions of the cerebrum and diencephalon. High levels of Dymple mRNA were found in cerebellar Purkinje cells and pontile giant neurons.
Using a yeast 2-hybrid system to identify proteins that interact with glycogen synthase kinase-3-beta (GSK3B; 605004), Hong et al. (1998) isolated a human fetal liver cDNA encoding DNM1L, which they called dynamin-like protein-4 (DYNIV). The deduced protein contains 699 amino acids.
Howng et al. (2004) identified 4 DYNIV splice variants that encode the full-length 736-amino acid protein and 699-, 710-, and 725-amino acid isoforms. All isoforms contain an N-terminal tripartite GTPase/GTP-binding site, and the shorter isoforms bear various in-frame deletions in their C-terminal halves relative to full-length DYNIV. RT-PCR detected variable expression of all 4 splice variants in 6 human cell lines examined.
Pitts et al. (2004) noted that DLP1 has a dynamin-like protein structure, with a conserved N-terminal GTPase domain, followed by a conserved middle domain, a nonconserved region, and a conserved C-terminal coiled-coil domain. Yoon (2010) stated that there are 12 splice variants of rat Dlp1 that encode proteins of 705 to 761 amino acids. The differential splicing results in changes within the GTPase and nonconserved domains.
Chang et al. (2010) reported that dimeric DRP1 has a predicted molecular mass of 180 kD and that the tetramer, formed by a dimer of dimers, has a predicted mass of 360 kD. Size-exclusion chromatography of HeLa cells expressing epitope-tagged DRP1 revealed 3 broad DRP1 peaks, representing dimers, tetramers, and higher-order DRP1 species that eluted in the void volume.
In mouse retina, Gerber et al. (2017) found expression of the Dnm1l gene in all plexiform layers, with strong expression in the ganglion cell axon layer, the pigmentary epithelium, and the choroid.
The dynamin superfamily of GTPases is divided into subfamilies on the basis of structural similarity. Members of the dynamin subfamily, including dynamin-1 (DNM1; 602377), dynamin-2 (DNM2; 602378), and dynamin-3 (DNM3; 611445), contain an N-terminal tripartite GTPase domain, a pleckstrin homology domain, and a C-terminal proline-rich region. Dynamin subfamily members have been shown to participate in clathrin-mediated endocytosis at the plasma membrane. Members of the dynamin-related subfamily, including the S. cerevisiae proteins Dnm1 and Vps1, contain the N-terminal tripartite GTPase domain but do not have the pleckstrin homology or proline-rich domains. Vps1 has been shown to play a role in vesicular transport from the late Golgi compartment to vacuoles, and Dnm1 is thought to be involved in endosomal trafficking. Furthermore, Dnm1 has been shown to be essential for the maintenance of mitochondrial morphology (Otsuga et al., 1998). Mitochondria exist as a dynamic tubular network with projections that move, break, and reseal in response to local environmental changes. Dnm1 is required for the cortical distribution of this network.
To determine the function of DRP1 (DNM1L), Smirnova et al. (1998) expressed mutant DRP1 in COS-7 cells. A mutation in the GTPase domain caused profound alterations in mitochondrial morphology. In cells expressing mutant DRP1, the tubular projections normally present in wildtype cells were retracted into large perinuclear aggregates. By electron microscopy, the mitochondrial aggregates appeared as clusters of tubules rather than as a large mass of coalescing membrane. The morphology of other organelles was unaffected by mutant DRP1. In addition, mutant DRP1 had no effect on the transport functions of the secretory and endocytic pathways. The authors proposed that DRP1 establishes mitochondrial morphology through a role in distributing mitochondrial tubules throughout the cytoplasm. They suggested that DRP1 is the functional equivalent of yeast Dnm1.
Imoto et al. (1998) demonstrated that overexpression of wildtype human DRP1 in mammalian cells increased secretion of a luciferase reporter protein, whereas overexpression of a GTP-binding site mutant of DRP1 decreased secretion of this marker.
Using an in vitro GTPase assay, Kamimoto et al. (1998) showed that a bacterially expressed DYMPLE fusion protein hydrolyzed GTP without additive modifications or coactivators.
Hong et al. (1998) showed that the C-terminal region of the 699-amino acid DYNIV protein bound to GSK3B.
Shin et al. (1999) found that DNM1L was oligomeric, probably tetrameric, under physiologic salt conditions, and that it aggregated into sedimentable complexes under low salt conditions. Analyses using the yeast 2-hybrid system and immunoprecipitation showed that the N-terminal and C-terminal regions of DNM1L could interact with each other.
Pitts et al. (1999) transiently transfected normal rat liver cells with wildtype rat Dlp1 and Dlp1 containing point mutations within conserved GTP-binding domains. Wildtype Dlp1 localized to distinct nonrandom foci along the length of mitochondria and in linear arrays on microtubules and the ER. Expression of the mutant proteins caused a pronounced collapse of mitochondria into the cell center. The ER of cells expressing mutant Dlp1 was also less distinct and appeared vesiculated.
Unlike the diffuse cytoplasmic distribution of wildtype DRP1, Santel and Fuller (2001) found that a GTPase-dead DRP1 mutant distributed to punctate structures in transfected COS-7 cells. In addition, mitochondria formed perinuclear aggregates similar to the aggregates formed in cells overexpressing mitofusin-2 (MFN2; 608507). COS-7 cells cotransfected with the GTPase-dead DRP1 and MFN2 developed mitochondrial tubules that extended from the perinuclear mitochondrial cluster towards the cell periphery. Santel and Fuller (2001) concluded that the size and morphologic arrangement of mitochondria are due to a dynamic balance between MFN-dependent mitochondrial fusion and DRP1-dependent mitochondrial fission.
Yoon et al. (2003) observed that human FIS1 (609003) and rat Dlp1 formed a complex in transfected cells and could interact with each other directly in vitro. These and other findings provided evidence that FIS1 regulates mitochondrial fission through a protein-protein interaction that recruits DLP1 from the cytosol to the mitochondrial surface.
Li and Gould (2003) showed that overexpression of PEX11-beta (PEX11B; 603867) in human fibroblasts induced peroxisome division in a multistep process involving elongation of preexisting peroxisomes followed by their division. They found that DLP1 was essential for the peroxisome division. The 710-amino acid DLP1 isoform, DLP1a, associated with peroxisomes, and PEX11-beta overexpression recruited DLP1a to peroxisome membranes. DLP1a and PEX11 proteins did not appear to interact directly.
By swapping domains between rat Dnm2 and rat Dlp1, Pitts et al. (2004) showed that the coiled-coil domain of Dlp1 conferred mitochondrial targeting to the protein. However, the mitochondria-specific function of Dlp1 also required the middle and nonconserved domains.
Jagasia et al. (2005) showed that Drp1, a key component of the mitochondrial fission machinery, was required and sufficient to induce mitochondrial fragmentation and programmed cell death during C. elegans development.
Germain et al. (2005) found that fluorescence-tagged rodent Drp1 was expressed in the cytosol of COS-7 cells, and that treatment of COS-7 and human cells with the apoptotic protein BIK (603392) resulted in recruitment of Drp1 to mitochondria prior to mitochondrial fragmentation. Drp1 maintained association with mitochondria during their initial shape change and following loss of mitochondrial potential and mobilization of cytochrome c (123970). Transmission electron microscopy showed that BIK expression caused profound opening of mitochondrial cristae, and these changes were inhibited by expression of a dominant-negative Drp1 mutant. Germain et al. (2005) concluded that DRP1 is involved in remodeling and opening of mitochondrial cristae during apoptosis, and that this function of DRP1 is distinct from its role in mitochondrial fission.
Type III, or necrosis-like, programmed cell death (PCD) is defined exclusively by cytoplasmic features and seems to operate in a caspase-independent manner. Bras et al. (2007) showed that ligation of CD47 (601028) triggered type III PCD in B cells from healthy volunteers and patients with chronic lymphocytic leukemia (CLL; 151400), and they identified DRP1 as a key mediator of this PCD. CD47 ligation induced DRP1 translocation from the cytosol to mitochondria. In mitochondria, DRP1 provoked impairment of the mitochondrial electron transport chain, resulting in dissipation of mitochondrial transmembrane potential, generation of reactive oxygen species, and a drop in ATP levels. Responsiveness of cells to CD47 ligation increased following DRP1 overexpression, while resistance to CD47-mediated death was observed following DRP1 downregulation. In CLL B cells, DRP1 mRNA levels strongly correlated with death sensitivity.
Cho et al. (2009) found that nitric oxide produced in response to beta-amyloid protein (104760), thought to be a key mediator of Alzheimer disease (see 104300), triggered mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of DRP1 (forming SNO-DRP1). Preventing nitrosylation of DRP1 by cysteine mutation abrogated these neurotoxic events. Cho et al. (2009) showed that SNO-DRP1 is increased in brains of human Alzheimer disease patients and may thus contribute to the pathogenesis of neurodegeneration.
Malena et al. (2009) tested the hypothesis that altering the balance between mitochondrial fusion and fission could influence the segregation of mutant and wildtype mtDNA variants, because it would modify the number of organelles per cell. Human cells heteroplasmic for the pathologic 3243A-G (MTTL1; 590050.0001) mitochondrial DNA mutation were transfected with constructs designed to silence DRP1 or human FIS1 (TTC11; 609003), whose gene products are required for mitochondrial fission. DRP1 and FIS1 gene silencing were both associated with increased levels of mutant mitochondrial DNA. The authors concluded that the extent of the mitochondrial reticular network appears to be an important factor in determining mutant load.
Using HeLa cells overexpressing DRP1, Chang et al. (2010) observed a kinetic lag between DRP1 self-assembly and GTP hydrolysis, suggesting that higher-order DRP1 multimers are required for maximal GTPase activity.
Huntington disease (HD; 143100) is a neurodegenerative disorder caused by abnormal expansion of a polyglutamine (polyQ) tract in huntingtin (HTT; 613004). Song et al. (2011) found mitochondrial abnormalities, including fragmentation, altered cristae morphology, and arrested intracellular movement, in fibroblasts from a patient with HD and in neurons of rodent models of HD. Immunoprecipitation of normal and HD human or mouse brain indicated that mutant, but not normal, huntingtin interacted with Drp1. In vitro assays with liposomes that mimicked the mitochondrial outer membrane revealed that mutant huntingtin stimulated Drp1 GTPase activity. Expression of a dominant-negative Drp1 mutant rescued mutant huntingtin-mediated mitochondrial fragmentation, defects in mitochondrial transport, and neuronal cell death. Electron microscopy showed that the normal ring- and spiral-like organization of DRP1 oligomers had an additional layer of density with the addition of mutant, but not normal, huntingtin.
Using Western blot analysis, Wang et al. (2011) found that the phosphorylated form of Drp1 accumulated in the cytosol of control neonatal rat cardiomyocytes, whereas the unphosphorylated form of Drp1 accumulated in mitochondria-enriched fractions following anoxia treatment. Drp1 translocation to mitochondria was associated with anoxia-induced mitochondrial fragmentation and apoptosis. Wang et al. (2011) characterized upstream events in this apoptotic pathway and found that p53 (TP53; 191170) downregulated expression of microRNA-499 (MIR499; 613614), which relieved Mir499-dependent repression of the calcineurin catalytic subunits Cna-alpha (PPP3CA; 114105) and Cna-beta (PPP3CB; 114106). Knockdown of either Cna-alpha or Cna-beta via small interfering RNA attenuated dephosphorylation-dependent Drp1 accumulation in mitochondria, mitochondria fragmentation, and anoxia-induced cell death.
Endoplasmic reticulum and mitochondria exhibit tightly coupled dynamics and have extensive contacts. In yeast and mammalian cells, Friedman et al. (2011) tested whether endoplasmic reticulum plays a role in mitochondrial division. They found that mitochondrial division occurred at positions where endoplasmic reticulum tubules contacted mitochondria and mediated constriction before Drp1 recruitment. Friedman et al. (2011) concluded that endoplasmic reticulum may play an active role in defining the position of mitochondrial division sites.
Wang et al. (2012) found that RIP1 (RIPK1; 603453), RIP3 (RIPK3; 605817), and MLKL (615153) formed a necrosis complex in human cell lines. Upon induction of necrosis by TNF-alpha (191160), both isoforms of PGAM5 (614939), PGAM5L and PGAM5S, interacted with the RIP1-RIP3-MLKL necrosis complex and were phosphorylated. Phosphorylated PGAM5S then recruited DRP1 and activated DRP1 by dephosphorylation, resulting in mitochondrial fragmentation and execution of necrosis. Blockade of phosphorylation or dephosphorylation signaling at several points in this signaling cascade, or knockdown of PGAM5 expression, blocked TNF-alpha-induced necrosis. Knockdown experiments showed that both PGAM5 isoforms and DRP1, but not RIP1, RIP3, or MLKL, were also involved in necrosis induced by reactive oxygen species or ionophore-mediated calcium shock.
Korobova et al. (2013) found that actin polymerization through endoplasmic reticulum (ER)-localized inverted formin-2 (INF2; 610982) was required for efficient mitochondrial fission in mammalian cells. INF2 functioned upstream of DRP1. Actin filaments appeared to accumulate between mitochondria and INF2-enriched ER membranes at constriction sites. Thus, INF2-induced actin filaments may drive initial mitochondrial constriction, which allows DRP1-driven secondary constriction.
Nagashima et al. (2020) found that microdomains of phosphatidylinositol 4-phosphate on trans-Golgi network vesicles were recruited to mitochondria-ER contact sites and can drive mitochondrial division downstream of DRP1. The loss of the small guanosine triphosphatase ADP-ribosylation factor-1 (ARF1; 103180) or its effector, phosphatidylinositol 4-kinase III-beta (PIK4CB; 602758), in different mammalian cell lines prevented phosphatidylinositol 4-phosphate generation and led to a hyperfused and branched mitochondrial network marked with extended mitochondrial constriction sites. Nagashima et al. (2020) concluded that recruitment of trans-Golgi network phosphatidylinositol 4-phosphate-containing vesicles at mitochondria contact sites may trigger final events leading to mitochondrial scission.
Howng et al. (2004) determined that the DNM1L gene contains 20 exons and spans 64 kb. Exons 15 and 16 are subject to differential splicing. The 5-prime flanking sequence contains 3 GC boxes that concatenate AP2 (TFAP2A; 107580)- and SP1 (189906)-binding motifs, but it lacks TATA or CAAT consensus sequences. Deletion analysis located the minimal promoter at nucleotides -108 to -100.
Cryoelectron Microscopy
Kalia et al. (2018) presented a cryoelectron microscopy structure of full-length human DRP1 coassembled with MID49 (615498) and an analysis of structure- and disease-based mutations. Kalia et al. (2018) reported that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signaling element, and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51 (615497). After coassembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening, and curling of DRP1 oligomers into constricted and closed rings. Kalia et al. (2018) concluded that together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.
By genomic sequence analysis, Howng et al. (2004) mapped the DNM1L gene to chromosome 12.
Encephalopathy due to Defective Mitochondrial and Peroxisomal Fission 1
In a newborn girl with a lethal encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Waterham et al. (2007) identified a de novo heterozygous dominant-negative mutation in the dynamin gene DLP1 (A395D; 603850.0001). The affected infant showed microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very long-chain fatty acids. Magnetic resonance imaging (MRI) detected an abnormal gyral pattern in both frontal lobes and was associated with dysmyelination. Death occurred at 37 days of age. Immunofluorescence microscopic analyses showed fewer peroxisomes in fibroblasts from the patient of Waterham et al. (2007) than in fibroblasts from control subjects. Furthermore, the peroxisomes from the patient varied markedly in size and were frequently arranged in rows. This arrangement was similar to that seen in mammalian cells overexpressing dominant-negative mutant DLP1 or those with DLP1 expression that had been downregulated owing to RNA interference (Koch et al., 2003; Li and Gould, 2003). Because such mammalian cells also showed a defect in mitochondrial fission (Smirnova et al., 2001; Yoon et al., 2001), Waterham et al. (2007) studied the mitochondria of fibroblasts from the patient using a fluorescent mitochondrial probe. Mitochondria in the patient's fibroblasts were elongated, tangled, tubular structures concentrated predominantly around the nucleus.
In a 7-year-old boy, born of unrelated Caucasian parents, with EMPF1, Vanstone et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (G362D; 603850.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a 2-year-old boy, born of unrelated Arab parents, with EMPF1, Sheffer et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (G362S; 603850.0003). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Transfection of the mutation into fibroblasts caused significantly altered mitochondrial morphology, with bulky clusters of mitochondria concentrated in a small area of the cell and absent in the remaining part. Transfected cells were also 60% smaller than control cells.
In 2 sibs, born of unrelated Filipino parents, with autosomal recessive EMPF resulting in death in early infancy (see EMPF1, 614388), Yoon et al. (2016) identified compound heterozygous truncating mutations in the DNM1L gene (603850.0004 and 603850.0005), The mutations were found by exome sequencing and segregated with the disorder in the family. Sural nerve samples revealed absent DNM1L protein in both patients compared to an age-matched control, consistent with a complete loss of function.
In a female infant with EMPF1, Vandeleur et al. (2019) identified a de novo heterozygous missense mutation in the DNM1L gene (E410K; 603850.0011). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing.
Optic Atrophy 5
In affected members from 3 unrelated French families with autosomal dominant optic atrophy-5 (OPA5; 610708), Gerber et al. (2017) identified 2 different heterozygous missense mutations in the DNM1L gene (E2A, 603850.0009 and A192E, 603850.0010). The mutations in the first 2 families were found by exome sequencing and confirmed by Sanger sequencing; the mutation in the third family was found by direct sequencing of the DNM1L gene. The mutations segregated with the disorder in all 3 families. Patient fibroblasts showed that the mutant proteins were expressed, were able to dimerize with wildtype DNM1L, and formed aggregates in both the cytoplasm and on the mitochondrial network. Mitochondria in mutant cells showed a highly elongated and tubulated network with a decrease in the number of mitochondrial extremities, suggesting an impairment of mitochondrial fission. In addition, DNM1L clusters were not associated with mitochondrial constriction sites in mutant fibroblasts. The findings were consistent with a dominant-negative effect. There were no structural differences of the peroxisomal network, nor alteration of the respiratory machinery. Heterozygous knockdown of the Dnm1l gene in mice (Dnm1l +/-) resulted in the elongation of the mitochondrial network of retinal ganglion cells, but no axonal degeneration in the optic nerve. Gerber et al. (2017) noted that OPA1 (165500), which has a similar phenotype, results from impaired mitochondrial fusion, suggesting that retinal ganglion cells are particularly sensitive to mitochondrial membrane dynamics.
Ishihara et al. (2009) found that Drp1 deletion in mice was embryonic lethal. Drp1 -/- embryos showed reduced development of the heart and liver, as well as thinned neural tube cell layer. Electron microscopy revealed that Drp1 -/- embryos had enlarged mitochondria with normal cristae and cytochrome c oxidase (see 516030) activity. Embryonic fibroblasts and stem cells from Drp1 -/- mice were healthy and proliferated normally. The ER and Golgi of Drp1 -/- cells appeared normal, but their mitochondria were abnormally extended and clustered near the nucleus. Peroxisomes were also swollen in Drp1 -/- cells. Cytokinesis in Drp1 -/- fibroblasts proceeded asymmetrically, with filamentous and highly clustered mitochondria cleaved at a constriction site of the cell in concert with cytokinesis and segregated unequally into the daughter cells. Treatment of Drp1 -/- cells with proapoptotic reagents suggested that Drp1 is involved in later apoptotic events, including cytochrome c release and caspase activation. Mice with neural cell-specific Drp1 deletion (NS-Drp1 -/- mice) died shortly after birth as a result of brain hypoplasia and apoptosis. Primary cultures of NS-Drp1 -/- mouse forebrain showed decreased number of neurites and defective synapse formation, suggesting that aggregated mitochondria fail to distribute properly within neural cell processes. NS-Drp1 -/- neuronal cells were also highly sensitive to Ca(2+)-dependent apoptosis.
Gerber et al. (2017) found that heterozygous knockdown of the Dnm1l gene in mice (Dnm1l +/-) resulted in the elongation of the mitochondrial network of retinal ganglion cells, but no axonal degeneration in the optic nerve.
In an infant with a lethal encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Waterham et al. (2007) found heterozygosity for a 1184C-A transversion in the DNM1L gene that resulted in an ala395-to-asp (A395D) substitution in the middle domain of the protein. The mutation was not found in genomic DNA from blood cells from either parent, indicating that the mutation either was de novo or was present only in germline cells of 1 parent. The patient presented in the first days of life with microcephaly, abnormal brain development, optic atrophy and hypoplasia, and lactic acidemia, and died at age 37 days. Overexpression of mutant DNM1L from the patient in fibroblasts from control subjects induced aberrant mitochondrial and peroxisomal phenotypes, indicating that the mutation acted in a dominant-negative manner.
By site-directed mutagenesis, Chang et al. (2010) created the A395D mutation, which falls in the middle domain of DRP1 that is critical for tetramer formation. Mutant DRP1, but not wildtype DRP1, caused dominant-negative elongation of mitochondria when overexpressed in HeLa cells. Mutant DRP1 was competent in tetramer assembly but defective in higher-order assembly. While wildtype DRP1 was predominantly in a higher-order form in solution, mutant DRP1 was mainly dimeric. Mutant DRP1 also showed a decreased rate of GTP hydrolysis compared with wildtype DRP1, and it did not show the kinetic lag between assembly and GTPase activity shown by wildtype DRP1. Chang et al. (2010) concluded that the markedly elongated mitochondria in cells expressing DRP1 with the A395D mutation is caused by decreased mitochondrial fission, likely because DRP1 cannot form higher-order complexes required for formation of fission complexes.
In a 7-year-old boy, born of unrelated Caucasian parents, with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Vanstone et al. (2016) identified a de novo heterozygous c.1085G-A transition (c.1085G-A, NM_012062.4) in exon 10 of the DNM1L gene, resulting in a gly362-to-asp (G362D) substitution in the middle domain, which is involved in homo-oligomerization. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. The patient had severely delayed psychomotor development and onset of refractory epilepsy at about 1 year of age. Confocal microscopy of patient fibroblasts showed hyperfusion of the mitochondrial network. However, respiratory chain enzymologies in muscle and skin fibroblasts and lactate/pyruvate ratio in fibroblasts were normal, as was serum lactate. There was no evidence of peroxisomal dysfunction. Vanstone et al. (2016) noted the diagnostic difficulties given that this patient had no clinical evidence of mitochondrial dysfunction on standard screening tests, and suggested that the disorder may result from abnormal mitochondrial distribution within neurons. Functional studies of the variant were not performed, but Vanstone et al. (2016) noted that Chang et al. (2010) had demonstrated that a mutation in an adjacent residue (G363D) compromised higher-order assembly and polymerization-dependent GTPase activity, suggesting pathogenicity.
In a 2-year-old boy, born of unrelated Arab parents, with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Sheffer et al. (2016) identified a de novo heterozygous c.1084G-A transition (c.1084G-A, NM_001278463) in the DNM1L gene, resulting in a gly362-to-ser (G362S) substitution at a highly conserved residue in the middle domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 132) database or an in-house database. Transfection of the mutation into fibroblasts caused significantly altered mitochondrial morphology, with bulky clusters of mitochondria concentrated in a small area of the cell and absent in the remaining part. The cells were also 60% smaller than control cells. Patient fibroblasts showed abnormally elongated mitochondria, mitochondrial complex IV deficiency, decreased ATP production, and decreased oxygen consumption; peroxisomes appeared to be unaffected.
In 2 infant sibs, born of unrelated parents of Filipino descent, with autosomal recessive encephalopathy due to defective mitochondrial and peroxisomal fission (see EMPF1, 614388), Yoon et al. (2016) identified compound heterozygous mutations in the DNM1L gene: a 1-bp duplication (c.261dup, NM_001278464.1), resulting in a frameshift and premature termination (Trp88MetfsTer9), and a 2-bp deletion (c.385_386del; 603850.0005), resulting in a frameshift and premature termination (Glu129LysfsTer6). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Variant Server databases. Each unaffected parent was heterozygous for 1 of the mutations. Sural nerve samples from both patients showed absence of the DNM1L protein compared to an age-matched control, consistent with a complete loss of function. The patients presented at birth with profound hypotonia, absent respiratory effort, no spontaneous movement, and areflexia; they both died in early infancy.
For discussion of the 2-bp deletion (c.385_386del, NM_001278464.1) in the DNM1L gene, resulting in a frameshift and premature termination (Glu129LysfsTer6), that was found in compound heterozygous state in 2 sibs with autosomal recessive encephalopathy due to defective mitochondrial and peroxisomal fission (see EPMF1, 614388) by Yoon et al. (2016), see 603850.0004.
In 2 brothers with autosomal recessive encephalopathy due to defective mitochondrial and peroxisomal fission (see EMPF1; 614388), Nasca et al. (2016) identified compound heterozygous mutations in the DNM1L gene: a 2-bp deletion (c.346_347delGA, NM_012062.4), resulting in a frameshift and premature termination (Glu116LysfsTer6) with loss of about 85% of the protein sequence, and a c.106A-G transition, resulting in a ser36-to-gly (S36G; 603850.0007) substitution in the GTPase domain. The mutations, which were found by targeted sequencing of a gene panel, were confirmed by Sanger sequencing and filtered against the 1000 Genomes Project and Exome Variant Server database. The S36G mutation was not found in the ExAC database, whereas the 2-bp deletion was found at a low frequency (0.004%) in ExAC. Each unaffected parent carried 1 of the mutations in heterozygous state. Western blot analysis of patient cells showed almost exclusive expression of the S36G mutant protein with decreased amounts of total DNM1L protein; the small deletion was likely subject to nonsense-mediated mRNA decay. Immunofluorescence studies showed that the mutant protein remained mainly cytoplasmic and did not localize to the mitochondria. Patient cells showed an elongated mitochondrial network consistent with impaired mitochondrial fission, which could be rescued by expression of wildtype DNM1L. Peroxisome morphology was also abnormal. Expression of the corresponding mutation (S39G) in yeast was associated with decreased oxidative growth, partial complex IV deficiency, increased mtDNA instability, and abnormal mitochondrial fission dynamics. The S36G mutation caused a partial loss of function, consistent with a hypomorphic allele and the recessive inheritance pattern in this family. Although immunofluorescence studies showed impairment of both mitochondria and peroxisomal dynamics, routine laboratory studies were not informative for these defects in the patients.
In 2 unrelated boys with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Fahrner et al. (2016) identified a de novo heterozygous c.1207C-T transition in the DNM1L gene, resulting in an arg403-to-cys (R403C) substitution in the middle domain, which is thought to be important for higher-order assembly into oligomeric rings. The mutations were found by whole-exome sequencing. In vitro expression studies in mouse embryonic fibroblasts and yeast showed that the R403C mutation results in impaired self-assembly and higher-order oligomerization, decreased colocalization to the mitochondria, and defective mitochondrial fission activity in a dominant-negative manner. The effects of this mutation were not as severe as those of A395D (603850.0001), which may explain the later onset of symptoms in these children at ages 4 and 5 years, respectively.
For discussion of the c.106A-G transition (c.106A-G, NM_012062.4) in the DNM1L gene, resulting in a ser36-to-gly (S36G) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive encephalopathy due to defective mitochondrial and peroxisomal fission (see EPMF1, 614388) by Nasca et al. (2016), see 603850.0005.
In a boy with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Chao et al. (2016) identified a de novo heterozygous c.1048G-A transition in the DNM1L gene, resulting in a gly350-to-arg (G350R) substitution at a highly conserved residue in the middle domain. The mutation, which was found by whole-exome sequencing, was not present in the father, but was present in maternal blood at a low level (6-8%), suggesting somatic mosaicism. The mutation was not present in the ExAC database. Transfection of the corresponding mutation into Drp1-null Drosophila was unable to rescue the embryonic lethal phenotype. Expression of the G350R mutation in Drosophila resulted in increased peroxisomal size, altered cellular distribution, decreased number of total peroxisomes per cell, abnormal mitochondrial morphology, and abnormal mitochondrial trafficking, with a dominant-negative effect.
In 13 affected members from 2 large multigenerational French families (families 1 and 2) with optic atrophy-5 (OPA5; 610708), Gerber et al. (2017) identified a heterozygous c.5A-C transversion (c.5A-C, NM_012062.3) in the DNM1L gene, resulting in a glu2-to-ala (E2A) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. One of the families (family 2) had previously been reported as 'family A' by Barbet et al. (2005). Patient fibroblasts showed evidence of impaired mitochondrial membrane fission.
In 3 members of a multigenerational French family (family 3) with optic atrophy-5 (OPA5; 610708), Gerber et al. (2017) identified a heterozygous c.575C-A transversion (c.575C-A, NM_012062.3) in the DNM1L gene, resulting in an ala192-to-glu (A192E) substitution at a highly conserved residue in the GTPase domain. The mutation, which was found by direct sequencing of the DNM1L gene, segregated with the disorder in the family. The family had previously been reported as 'family B' by Barbet et al. (2005). Patient fibroblasts showed evidence of impaired mitochondrial membrane fission.
In a female infant with lethal encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Vandeleur et al. (2019) identified a de novo heterozygous c.1228G-A transition in coding exon 11 of the DNM1L gene (E410K; 603850.0011), resulting in a glu410-to-lys (E410K) substitution at a highly conserved residue in a domain that is important for tetramerization. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The variant was not found in population databases. Functional studies were not performed. Clinical features in the patient included decreased visual tracking, cardiomyopathy, developmental delay, and hypotonia. She died at 8 months of age of congestive heart failure and cardiogenic shock. Postmortem evaluation showed mitochondrial cardiomyopathy characterized by abnormal cardiac myocytes with enlarged mitochondria. Neuropathology showed accumulation of intracellular organelles, such as mitochondria, in the midbrain, cerebellum, and pons as well as reduction in myelination in the subcortical white matter.
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