Nach 7 Monaten habe ich nun meinen Befunde der zweiten Exomsequenzierung erhalten. Die Untersuchung wurde vom Mito-Experten Prof. Freisinger unter der klinischen Verdachtsdiagnose mitochondriale Enzephalomyopathie, MNGIE-like in Auftrag gegeben.
Erwartet habe ich mir nicht allzu viel, da bereits die erste Exomsequenzierung keine eindeutig pathogene Variante identifizieren konnte, aber das Team hat laut Prof. Freisinger höhere Detektionsraten von bis 40% in der Kohorte der Patienten mit angeborenen Stoffwechselerkrankungen inklusive Mitochondriopathien.
Und wie erwartet konnte keine eindeutig pathogene Variante identifiziert werden. Allerdings wurden zwei Veränderungen unklarer Signifikanz (Klasse 3: also Varianten, bei denen weder mit hoher Wahrscheinlichkeit eine Pathogenität ausgeschlossen noch angenommen werden kann) gefunden. Eine, die das Krankheitsbild als Ganzes nicht erklären kann - sie wurde bisher beschrieben bei zerebellärer Ataxie mit kognitiven Entwicklungsstörungen bzw. Epilepsie oder Bewegungsstörungen. Und dann eine ebenfalls der Klasse 3, die laut Labor mit Chromosomenanalyse weiter abgeklärt werden sollte, eine jeweils mehrere Kilobasen umfassende Duplikation auf Chromosom 1 sowie Chromosom 20.
Diese enthalten mehrere Gene, von den meisten habe ich den Namen noch nie gelesen/gehört.
Chromosom 20: BCL2L1, COX4I2, DEFB118, DEFB119, DEFB121, DEFB123,DEFB124, DUSP15, FOXS1, HCK, HM13, ID1, MYLK2,PDRG1, REM1, TPX2, TTLL9
Chromosom 1: AKR1A1. CCDC17, IPP, MAST2, MMACHC, NASP, PRDX1
Auf den ersten Blick fiel mir COX4I2 auf, denn das hat etwas mit der mitochondrialen Atmungskette zu tun:
"....Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]
From UniProt:
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunbit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix..."
Aus Wiki:
"...Although relatively little is known about the function of COX4I1, mutations in this gene have been associated with mitochondrial complex IV diseases with severe phenotypes. Among these, COX deficiency and Fanconi anemia have been suspected and linked to mutations in the COX4I1 gene. Clinical features of pathogenic variants of COX4I1 can include short stature, poor weight gain, mild dysmorphic features, mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched palate, malar hypoplasia, little subcutaneous fat, and arachnodactyly. The homozygous mutation K101N and a de novo 16q24.1 interstitial duplication have been found to cause defective COX4I1..."
Zu dem BCL2L1-Gen: https://www.genecards.org/cgi-bin/ca...pl?gene=BCL2L1
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The proteins encoded by this gene are located at the outer mitochondrial membrane, and have been shown to regulate outer mitochondrial membrane channel (VDAC) opening. VDAC regulates mitochondrial membrane potential, and thus controls the production of reactive oxygen species and release of cytochrome C by mitochondria, both of which are the potent inducers of cell apoptosis. Alternative splicing results in multiple transcript variants encoding two different isoforms. The longer isoform acts as an apoptotic inhibitor and the shorter isoform acts as an apoptotic activator. [provided by RefSeq, Dec 2015]
BCL2L1 (BCL2 Like 1) is a Protein Coding gene. Diseases associated with BCL2L1 include T-Cell Leukemia and Follicular Lymphoma. Among its related pathways are Amyotrophic lateral sclerosis (ALS) and CDK-mediated phosphorylation and removal of Cdc6. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and protein heterodimerization activity. An important paralog of this gene is BCL2...."#
Zu MYLK2: https://www.genecards.org/cgi-bin/ca....pl?gene=MYLK2
"
MYLK2 (Myosin Light Chain Kinase 2) is a Protein Coding gene. Diseases associated with MYLK2 include Cardiomyopathy, Familial Hypertrophic, 1 and Hypertrophic Cardiomyopathy. Among its related pathways are Oxytocin signaling pathway and Salivary secretion. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is MYLK3.
REM1:
https://www.genecards.org/cgi-bin/carddisp.pl?gene=REM1
"...
REM1 (RRAD And GEM Like GTPase 1) is a Protein Coding gene. Diseases associated with REM1 include Mobitz Type Ii Atrioventricular Block and Parkinson Disease, Late-Onset. Gene Ontology (GO) annotations related to this gene include GTP binding and ferrous iron transmembrane transporter activity. An important paralog of this gene is RRAD.
..
Die anderen Gene sind wohl zu vernachlässigen. Keine Ahnung, ob diese in Kombo eine Mito bzw. Mito-ähnliches Krankheitsbild verursachen könnten....
Mal sehen, ob ich das Angebot der gen. Beratung mit anschließender Chromosomenuntersuchung in Ansprach nehme. Müsste dafür ja extra nach Tübingen.
Erwartet habe ich mir nicht allzu viel, da bereits die erste Exomsequenzierung keine eindeutig pathogene Variante identifizieren konnte, aber das Team hat laut Prof. Freisinger höhere Detektionsraten von bis 40% in der Kohorte der Patienten mit angeborenen Stoffwechselerkrankungen inklusive Mitochondriopathien.
Und wie erwartet konnte keine eindeutig pathogene Variante identifiziert werden. Allerdings wurden zwei Veränderungen unklarer Signifikanz (Klasse 3: also Varianten, bei denen weder mit hoher Wahrscheinlichkeit eine Pathogenität ausgeschlossen noch angenommen werden kann) gefunden. Eine, die das Krankheitsbild als Ganzes nicht erklären kann - sie wurde bisher beschrieben bei zerebellärer Ataxie mit kognitiven Entwicklungsstörungen bzw. Epilepsie oder Bewegungsstörungen. Und dann eine ebenfalls der Klasse 3, die laut Labor mit Chromosomenanalyse weiter abgeklärt werden sollte, eine jeweils mehrere Kilobasen umfassende Duplikation auf Chromosom 1 sowie Chromosom 20.
Diese enthalten mehrere Gene, von den meisten habe ich den Namen noch nie gelesen/gehört.
Chromosom 20: BCL2L1, COX4I2, DEFB118, DEFB119, DEFB121, DEFB123,DEFB124, DUSP15, FOXS1, HCK, HM13, ID1, MYLK2,PDRG1, REM1, TPX2, TTLL9
Chromosom 1: AKR1A1. CCDC17, IPP, MAST2, MMACHC, NASP, PRDX1
Auf den ersten Blick fiel mir COX4I2 auf, denn das hat etwas mit der mitochondrialen Atmungskette zu tun:
"....Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]
From UniProt:
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunbit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix..."
Aus Wiki:
"...Although relatively little is known about the function of COX4I1, mutations in this gene have been associated with mitochondrial complex IV diseases with severe phenotypes. Among these, COX deficiency and Fanconi anemia have been suspected and linked to mutations in the COX4I1 gene. Clinical features of pathogenic variants of COX4I1 can include short stature, poor weight gain, mild dysmorphic features, mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched palate, malar hypoplasia, little subcutaneous fat, and arachnodactyly. The homozygous mutation K101N and a de novo 16q24.1 interstitial duplication have been found to cause defective COX4I1..."
Zu dem BCL2L1-Gen: https://www.genecards.org/cgi-bin/ca...pl?gene=BCL2L1
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The proteins encoded by this gene are located at the outer mitochondrial membrane, and have been shown to regulate outer mitochondrial membrane channel (VDAC) opening. VDAC regulates mitochondrial membrane potential, and thus controls the production of reactive oxygen species and release of cytochrome C by mitochondria, both of which are the potent inducers of cell apoptosis. Alternative splicing results in multiple transcript variants encoding two different isoforms. The longer isoform acts as an apoptotic inhibitor and the shorter isoform acts as an apoptotic activator. [provided by RefSeq, Dec 2015]
BCL2L1 (BCL2 Like 1) is a Protein Coding gene. Diseases associated with BCL2L1 include T-Cell Leukemia and Follicular Lymphoma. Among its related pathways are Amyotrophic lateral sclerosis (ALS) and CDK-mediated phosphorylation and removal of Cdc6. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and protein heterodimerization activity. An important paralog of this gene is BCL2...."#
Zu MYLK2: https://www.genecards.org/cgi-bin/ca....pl?gene=MYLK2
"
MYLK2 (Myosin Light Chain Kinase 2) is a Protein Coding gene. Diseases associated with MYLK2 include Cardiomyopathy, Familial Hypertrophic, 1 and Hypertrophic Cardiomyopathy. Among its related pathways are Oxytocin signaling pathway and Salivary secretion. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is MYLK3.
- Implicated in the level of global muscle contraction and cardiac function. Phosphorylates a specific serine in the N-terminus of a myosin light chain.
REM1:
https://www.genecards.org/cgi-bin/carddisp.pl?gene=REM1
"...
- The protein encoded by this gene is a GTPase and member of the RAS-like GTP-binding protein family. The encoded protein is expressed in endothelial cells, where it promotes reorganization of the actin cytoskeleton and morphological changes in the cells. [provided by RefSeq, Jul 2008
REM1 (RRAD And GEM Like GTPase 1) is a Protein Coding gene. Diseases associated with REM1 include Mobitz Type Ii Atrioventricular Block and Parkinson Disease, Late-Onset. Gene Ontology (GO) annotations related to this gene include GTP binding and ferrous iron transmembrane transporter activity. An important paralog of this gene is RRAD.
..
Die anderen Gene sind wohl zu vernachlässigen. Keine Ahnung, ob diese in Kombo eine Mito bzw. Mito-ähnliches Krankheitsbild verursachen könnten....
Mal sehen, ob ich das Angebot der gen. Beratung mit anschließender Chromosomenuntersuchung in Ansprach nehme. Müsste dafür ja extra nach Tübingen.
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