Chybějící geny

DNAJB6

A co-chaperone of HSP70
X cause limb girdle muscular dystrophy (LGMD) D1
No treatments are currently available
Two isoforms exist, DNAJB6a and DNAJB6b

Each with distinct localizations in muscle

Mutations reside in both isoforms

DNAJB6b is primarily responsible for disease pathogenesis

DNAJB6 knockout is embryonic lethal
Isoform-specific knockdown
Isoform specific knockdown in LGMDD1 - primary myotube cultures from a knockin LGMDD1 mouse model

LGMDD1 protein signature related to protein homeostasis and myofibril structure

Selective reduction of DNAJB6b levels in LGMDD1 myotubes

Corrected much of the proteomic disease signature toward wild type levels

Wide age range of onset
May have either a proximal or distal predominant pattern of weakness
Biopsies demonstrate

A vacuolar myopathy with aggregates
Myofibrillar abnormalities involving the Z disc.

Standard of care is supportive in nature
Ubiquitously transcribed co-chaperone of HSP70 with a wide array of functions

Tumor suppressor,
Prevents aggregation of polyglutamine-containing proteins
Role in viral replication cycles
Cause a degenerative disorder of skeletal muscle

Absence of DNAJB6 manifests differently and is embryonic lethal in mice
Mutations associated with LGMDD1 are located in regions of DNAJB6 that affect both isoforms
Zebrafish injected with mutant human DNAJB6b mRNA resulted in myofibrillar abnormalities

Mutant DNAJB6a mRNA did not

Haploinsufficiency

May be tolerated
Associated with a sick sinus syndrome phenotype in mice with no structural cardiac changes
www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(23)00135-X

DNAJB6b is Downregulated in Synucleinopathies

DNAJB6 is highly upregulated in Parkinsonian astrocytes, which might reflect a protective reaction
The anti-amyloidogenic chaperone DNAJB6
Loss of expression of the anti-amyloidogenic chaperone DNAJB6

Upon glutamate treatment, aggregates form in neurons

Upregulation of DNAJB6 in neurons

Antagonizes glutamate-induced aggregation

Knockdown of DNAJB6 in progenitors

Results in spontaneous polyglutamine aggregation

Loss of DNAJB6 expression upon differentiation is confirmed in vivo

Explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons.

DNAJB6

Prevent poly-Q dependent protein aggregation and cellular toxicity induced by the mutant huntingtin protein

PDNAJB6 was found to be significantly upregulated by PCV2 infection
Heat shock protein Hsp40/DNAJ family
DNAJB6b promotes cytoplasmic accumulation of the viral primase of CMV
DNAJB6a enhances nuclear distribution of a herpesvirus primase

Deficit = výhoda v případě infekce CMV

DNAJB6 has been shown to interact with keratin
Aggregation of Abeta42 (a process involved in e.g. Alzheimer's disease) is retarded by DNAJB6 in a concentration-dependent manner
Dominant mutations in DNAJB6

Late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1)
Characterized by protein aggregation and vacuolar myopathology

en.wikipedia.org/wiki/DNAJB6
Molecular chaperone for neuronal proteins including huntingtin (PubMed:11896048, 22366786).
TDP-43 is a client protein of DNAJB6

Dipeptidyl-peptidase–like protein 6 (DPPX) deficit

DPPX/Kv4.2 potassium channels
Somatodendritic signal integration
Attenuation of back-propagation of action potentials
Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.
X disorders characterized by cognitive inflexibility is described
Dipeptidyl aminopeptidase-like protein DPPX (DPP6)

Associates with Kv4 potassium channels
Increasing surface trafficking and reconstituting native neuronal ISA-like properties

Dipeptidyl peptidase 10 (DPP10)

Shares with DPP6 a high amino acid identity
Lack of enzymatic activity
Expression predominantly in the brain
DPP10 is a potent modulator of Kv4 expression and biophysical properties

May be a critical component of somatodendritic ISA channels in the brain.

www.semanticscholar.org/paper/Modulation-of-Kv4.2-channel-expression-and-gating-Jerng-Qian/eaa4bf228e629e93be76c8ec7889571a1d0d1036

Antibody–associated encephalitis IgG subclass effects x DPPX

9 patients were identified (median age 57 years, range 36–69 years)
Severe prodromal weight loss or diarrhea followed by cognitive dysfunction (9), memory deficits (5), CNS hyperexcitability

(8; hyperekplexia, myoclonus, tremor, or seizures)
Or brainstem or cerebellar dysfunction (7)

The peak of the disease was reached 8 months (range 1–54 months) after onset
All patients had both IgG4 and IgG1 DPPX antibodies
Kv4.2 protein that was reversible on removal of the antibodies
Reported cases (total 39)

67% developed the triad

Weight loss (median 20 kg; range 8–53 kg)/gastrointestinal symptoms,
cognitive-mental dysfunction
CNS hyperexcitability

35 patients (8 not treated with immunotherapy)

60% had substantial or moderate improvement
23% had no improvement (most of them not treated)
17% died
Relapses in 8 of 35 patients (23%) and were responsive to immunotherapy.

www.ncbi.nlm.nih.gov/pmc/articles/PMC5379928/
Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4-mediated A-type K+ channels
www.semanticscholar.org/paper/Dipeptidyl%E2%80%90peptidase%E2%80%90like%E2%80%90proteins-confer-high-to-Maffie-Dvoretskova/30feddcab95f72e815c08bd4abc1f3bef3895720

Kv4.2 KO mice

Had cognitive deficits in learning and memory (Lugo et al., 2012)
www.sciencedirect.com/science/article/abs/pii/S0197018621002011

Kv4.2

Could promote the proliferations of neural stem cells
Induce the neural stem cells to differentiate into neurons in vitro and in vivo.
Kv4.2 could up-regulate the expressions of ERK1/2, p-ERK1/2, p-STAT3, NGF, p-TrkA, and BDNF, CAMKII and the concentration of intracellular Ca2+.
Kv4.2 promoted neurogenesis through ++ERK1/2/STAT3, NGF/TrkA, Ca2+/CAMKII signal pathways++ and rescued the ischemic impairments.
www.sciencedirect.com/science/article/abs/pii/S0197018621002011

Magnesium Deficiency

Causes Transcriptional Downregulation of Kir2.1 and Kv4.2 Channels in Cardiomyocytes Resulting in QT Interval Prolongation
www.jstage.jst.go.jp/article/circj/84/8/84_CJ-20-0310/_pdf

Problematické geny

FOXP2 (Forkhead Box P2)

Haploinsufficiency of FOXP2 is associated with language and speech disorders.
This gene plays a crucial role in the development of neural circuits involved in language.

SLC25A13 (Solute Carrier Family 25 Member 13)

Mutations or deletions in SLC25A13 can lead to citrullinemia

Autosomal recessive disorder affecting urea cycle metabolism

Haploinsufficiency may contribute to milder metabolic disturbances.

VLDLR (Very Low-Density Lipoprotein Receptor)

In lipoprotein metabolism, and haploinsufficiency may impact cholesterol homeostasis.
Haploinsufficiency of VLDLR has been associated with cerebellar hypoplasia and a milder form of the lissencephaly syndrome.

GLI3 (GLI Family Zinc Finger 3)

Mutations in GLI3 can cause Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome.
Haploinsufficiency of GLI3 is associated with limb abnormalities and craniofacial defects.

CDK13 (Cyclin-Dependent Kinase 13)

Haploinsufficiency of CDK13 has been associated with developmental disorders and intellectual disabilities.
Mutations in CDK13 have been associated with developmental disorders and intellectual disabilities.
Haploinsufficiency of CDK13 may contribute to these conditions.

METTL21A (Methyltransferase Like 21A)

Information on haploinsufficiency for METTL21A might be limited
Genes involved in methylation processes can play critical roles in various cellular functions, and disruptions may impact gene expression regulation.

KMT2E (Lysine Methyltransferase 2E)

Mutations in KMT2E have been associated with intellectual disabilities and developmental disorders.
Haploinsufficiency of KMT2E may contribute to these conditions.

DLX5 (Distal-Less Homeobox 5)

DLX5 is involved in embryonic development and mutations can lead to developmental disorders.
Haploinsufficiency may contribute to craniofacial and limb abnormalities.

NRCAM (Neuronal Cell Adhesion Molecule)

Mutations or haploinsufficiency of NRCAM have been associated with neurodevelopmental disorders, including autism spectrum disorders.

SP4 (Sp4 Transcription Factor)

SP4 is a transcription factor involved in neural development, and disruptions may contribute to intellectual disabilities and developmental disorders.

GLI2 (GLI Family Zinc Finger 2)

Mutations in GLI2 have been associated with various developmental disorders, including holoprosencephaly.
Haploinsufficiency may contribute to craniofacial and neurological abnormalities.

SEPT9 (Septin 9)

Mutations in SEPT9 have been associated with hereditary neuralgic amyotrophy, a disorder affecting peripheral nerves.
Haploinsufficiency may contribute to neurological symptoms.

PRSS12 (Serine Protease 12)

Information about haploinsufficiency for PRSS12 might be limited,
serine proteases play crucial roles in various biological processes, and disruptions may affect protein digestion and other functions.

FSCN1 (Fascin Actin-Bundling Protein 1)

Mutations in FSCN1 have been associated with fascin-related hypertrophic cardiomyopathy.
Haploinsufficiency may contribute to cardiac abnormalities.

RNF216 (Ring Finger Protein 216)

Mutations in RNF216 have been associated with intellectual disabilities and developmental disorders.
Haploinsufficiency of RNF216 may contribute to these conditions.

HMGN2 (High Mobility Group Nucleosomal Binding Domain 2)

Haploinsufficiency of HMGN2 may impact chromatin structure and gene expression regulation, potentially contributing to developmental or neurological disorders.

THSD7B (Thrombospondin Type 1 Domain Containing 7B)

Mutations in THSD7B have been associated with developmental disorders, including intellectual disabilities and autism.
Haploinsufficiency may contribute to these conditions.

AKAP9 (A-Kinase Anchoring Protein 9)

Mutations in AKAP9 have been associated with intellectual disabilities and developmental disorders.
Haploinsufficiency may contribute to these conditions.

PRSS16 (Serine Protease 16)

Specific information about haploinsufficiency for PRSS16 might be limited
serine proteases play roles in various biological processes, and disruptions may have consequences for protein digestion and other functions.

MEOX1 (Mesenchyme Homeobox 1)

Mutations in MEOX1 have been associated with Klippel-Feil syndrome, a disorder affecting the development of the spine.
Haploinsufficiency may contribute to skeletal abnormalities.

CALCR (Calcitonin Receptor)

The function of CALCR is associated with the regulation of calcium homeostasis
Haploinsufficiency may impact bone metabolism and calcium regulation.

NOMO1 (NODAL Modulator 1)

NOMO1 is associated with the regulation of NODAL signaling, which plays a role in embryonic development.
Haploinsufficiency may contribute to developmental abnormalities.

VIPR2 (Vasoactive Intestinal Peptide Receptor 2)

Disruptions in VIPR2 may affect vasoactive intestinal peptide signaling, potentially influencing various physiological processes.
Haploinsufficiency may contribute to imbalances in these processes.

CDK6 (Cyclin-Dependent Kinase 6)

CDK6 is a cell cycle regulator,
Haploinsufficiency may impact cell division and proliferation.

Dohledáno via CHAT GPT

FOXP2: The FOXP2 gene in this region is associated with language development. Its deletion could potentially contribute to language and communication challenges.
IMMP2L: This gene is involved in mitochondrial function. Disruptions in IMMP2L could potentially impact cellular energy metabolism.
LHFPL3: Little is known about the exact function of this gene, and its specific role in metabolism may not be well-documented.
CALD1: CALD1 is associated with smooth muscle contraction. Its deletion might impact the function of smooth muscle cells in various organs.
CUL1: CUL1 is involved in protein degradation and may play a role in cellular homeostasis.DLX5: This gene is involved in embryonic development and plays a role in the development of bones and the central nervous system.
DLX6: Like DLX5, DLX6 is also involved in embryonic development and is associated with the development of facial structures and limbs.
IMMP2L (Inner Mitochondrial Membrane Peptidase Subunit 2-Like): This gene is involved in mitochondrial function and may play a role in cellular energy metabolism.
MDFIC (MyoD Family Inhibitor Domain Containing): MDFIC is involved in the regulation of muscle differentiation and may have roles in muscle development.
MEOX1 (Mesenchyme Homeobox 1): MEOX1 is a homeobox-containing gene involved in the regulation of embryonic development and differentiation.
RASA4 (RAS P21 Protein Activator 4): RASA4 is associated with the regulation of Ras signaling, which plays a role in various cellular processes.
PRSS16 (Serine Protease 16): This gene encodes a serine protease and may have roles in protein digestion and other processes.
CALD1 (Caldesmon 1): CALD1 is associated with smooth muscle contraction and may play a role in the regulation of smooth muscle cells in various tissues.
ZNF711 (Zinc Finger Protein 711): ZNF711 is a zinc finger protein involved in transcriptional regulation.
ZNF451 (Zinc Finger Protein 451): This gene encodes a zinc finger protein and may play a role in transcriptional regulation.
SLC25A13 (Solute Carrier Family 25 Member 13): This gene encodes a mitochondrial ornithine transporter and is associated with citrullinemia, a disorder of urea cycle metabolism.
NRCAM (Neuronal Cell Adhesion Molecule): NRCAM is involved in neuronal cell adhesion and may play a role in the development and function of the nervous system.
VIPR2 (Vasoactive Intestinal Peptide Receptor 2): This gene encodes a receptor for vasoactive intestinal peptide (VIP) and may be involved in various physiological processes, including smooth muscle relaxation.
FOXP2 (Forkhead Box P2): FOXP2 is involved in speech and language development and has been associated with language disorders. Its deletion can contribute to language and communication challenges.
NUPL2 (Nucleoporin Like 2): NUPL2 is associated with nucleocytoplasmic transport and may have roles in cellular processes related to gene expression.
CDK6 (Cyclin-Dependent Kinase 6): CDK6 is a cell cycle regulator that plays a role in cell division and proliferation.
CDK13 (Cyclin-Dependent Kinase 13): CDK13 is another member of the cyclin-dependent kinase family and is involved in the regulation of transcription.
METTL10 (Methyltransferase Like 10): This gene is associated with methyltransferase activity and may play a role in RNA processing.
FSCN1 (Fascin Actin-Bundling Protein 1): FSCN1 is involved in the bundling of actin filaments and may play a role in cellular structure and motility.
PAM (Peptidylglycine Alpha-Amidating Monooxygenase): PAM is involved in the amidation of peptide hormones and neurotransmitters.
HMGN2 (High Mobility Group Nucleosomal Binding Domain 2): HMGN2 is associated with nucleosome binding and may play a role in chromatin structure and gene expression regulation.
KMT2E (Lysine Methyltransferase 2E): This gene is involved in histone methylation and may play a role in epigenetic regulation.
CCDC39 (Coiled-Coil Domain Containing 39): CCDC39 is associated with ciliary function and may be involved in ciliopathies and respiratory ciliary function.
NOMO1 (NODAL Modulator 1): NOMO1 is associated with the regulation of NODAL signaling, which plays a role in embryonic development.
AKAP9 (A-Kinase Anchoring Protein 9): AKAP9 is associated with anchoring protein kinase A and may play a role in the regulation of cellular processes.
CALCR (Calcitonin Receptor): CALCR is involved in the regulation of calcium homeostasis and may play a role in bone metabolism.
CUX2 (Cut Like Homeobox 2): CUX2 is associated with neuronal development and may play a role in the development of the cerebral cortex.
GLI3 (GLI Family Zinc Finger 3): GLI3 is involved in the Hedgehog signaling pathway and plays a role in limb development.
SEPT9 (Septin 9): SEPT9 is a member of the septin family and may be involved in cytokinesis and cellular morphology.
METTL21A (Methyltransferase Like 21A): METTL21A is associated with methyltransferase activity and may play a role in RNA processing.
PRSS12 (Serine Protease 12): PRSS12 is associated with serine protease activity and may play a role in protein digestion.
SP4 (Sp4 Transcription Factor): SP4 is a transcription factor involved in the regulation of gene expression and may play a role in neural development.
THSD7B (Thrombospondin Type 1 Domain Containing 7B): THSD7B is associated with thrombospondin type 1 domain and may play a role in vascular development.
VLDLR (Very Low-Density Lipoprotein Receptor): VLDLR is involved in lipoprotein metabolism and may play a role in cholesterol homeostasis.
RNF216 (Ring Finger Protein 216): RNF216 is associated with ubiquitin ligase activity and may be involved in protein degradation.
LOC105371702 (Uncharacterized protein LOC105371702): The function of this protein is currently uncharacterized.
LOC105370121 (Uncharacterized protein LOC105370121): The function of this protein is currently uncharacterized.
LOC105370123 (Uncharacterized protein LOC105370123): The function of this protein is currently uncharacterized.
LOC101929393 (Uncharacterized protein LOC101929393): The function of this protein is currently uncharacterized.
LOC105371873 (Uncharacterized protein LOC105371873): The function of this protein is currently uncharacterized.

HMGN2 (High Mobility Group Nucleosomal Binding Domain 2): HMGN2 is associated with nucleosome binding and may play a role in chromatin structure and gene expression regulation.
KMT2E (Lysine Methyltransferase 2E): This gene is involved in histone methylation and may play a role in epigenetic regulation.
CCDC39 (Coiled-Coil Domain Containing 39): CCDC39 is associated with ciliary function and may be involved in ciliopathies and respiratory ciliary function.
NOMO1 (NODAL Modulator 1): NOMO1 is associated with the regulation of NODAL signaling, which plays a role in embryonic development.
AKAP9 (A-Kinase Anchoring Protein 9): AKAP9 is associated with anchoring protein kinase A and may play a role in the regulation of cellular processes.
CALCR (Calcitonin Receptor): CALCR is involved in the regulation of calcium homeostasis and may play a role in bone metabolism.
CUX2 (Cut Like Homeobox 2): CUX2 is associated with neuronal development and may play a role in the development of the cerebral cortex.
GLI3 (GLI Family Zinc Finger 3): GLI3 is involved in the Hedgehog signaling pathway and plays a role in limb development.
SEPT9 (Septin 9): SEPT9 is a member of the septin family and may be involved in cytokinesis and cellular morphology.
METTL21A (Methyltransferase Like 21A): METTL21A is associated with methyltransferase activity and may play a role in RNA processing.
GLI2 (GLI Family Zinc Finger 2): GLI2 is a transcription factor involved in the Hedgehog signaling pathway and may play a role in various developmental processes.
LOC105371852 (Uncharacterized protein LOC105371852): The function of this protein is currently uncharacterized.LOC105370099 (Uncharacterized protein LOC105370099): The function of this protein is currently uncharacterized.LOC105371940 (Uncharacterized protein LOC105371940): The function of this protein is currently uncharacterized.LOC105371954 (Uncharacterized protein LOC105371954): The function of this protein is currently uncharacterized.LOC105371960 (Uncharacterized protein LOC105371960): The function of this protein is currently uncharacterized.LOC105371970 (Uncharacterized protein LOC105371970): The function of this protein is currently uncharacterized.LOC105371985 (Uncharacterized protein LOC105371985): The function of this protein is currently uncharacterized.LOC105372000 (Uncharacterized protein LOC105372000): The function of this protein is currently uncharacterized.LOC105372004 (Uncharacterized protein LOC105372004): The function of this protein is currently uncharacterized.

MUDr. Dana Maňasková