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Report for Clinical Trial NCT03999788

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Clinical Relevance of miR-142-3p as Potential Biomarker of Synaptopathy in Multiple Sclerosis

Inflammatory synaptopathy is a prominent pathogenic mechanism in multiple sclerosis (MS) and in its mouse model, which can cause excitotoxic damage by long-lasting excessive synaptic excitation and, consequentially, drives disease progression by leading to motor and cognitive deficits. As synaptopathy occurs early during the disease course and is potentially reversible, it represents an appealing therapeutic target in MS. Although reliable biomarkers of MS synaptopathy are still missing, recent researches highlighted miR-142-3p as a possible candidate. Indeed, miR-142-3p has been described to promote the IL-1beta-dependent synaptopathy by downregulating GLAST/EAAT1, a crucial glial transporter involved in glutamate homeostasis. Furthermore, mir-142-3p has been suggested as a putative negative MS prognostic factor and a target of current MS disease modifying therapies. The hypothesis of this study is that miR-142-3p represents a good biomarker for excitotoxic synaptopathy to predict MS course, and, possibly, treatment efficacy at individual level, including both pharmacological strategies and non-pharmacological interventions, like therapeutic transcranial magnetic stimulation (TMS) to ameliorate MS spasticity. To this aim, the role of miR-142-3p in MS synaptopathy, its potential impact on the efficacy of disease-modifying treatments currently used in MS therapy as well as the influence of genetic variants (SNPs) of miR-142-3p and GLAST/EAAT1 coding genes on the responsiveness to therapeutic TMS, will be further investigated in the study. By validating miR-142-3p as potential biomarker of synaptopathy, it is expect to improve MS prognosis and personalized therapies. Patients with MS, who will undergo neurological assessment, conventional brain MRI scan, and CSF and blood withdrawal for diagnostic and clinical reasons at the Neurology Unit of IRCCS INM-Neuromed will be enrolled in the study. Neurophysiological, biochemical and genetic parameters together with lower limb spasticity will be evaluated. Subjects, who will undergo blood sampling and/or lumbar puncture for clinical suspicions, later on not confirmed, will be recruited as control group. A subgroup of MS patients showing lower limb spasticity will be included in a two-week repetitive TMS stimulation protocol (iTBS) to correlate the patient responsiveness to this non-pharmacological treatment with MS-significant SNPs of both miR-142-3p and GLAST/EAAT1 coding genes.

NCT03999788 Multiple Sclerosis Spasticity
MeSH:Muscle Spasticity Multiple Sclerosis Sclerosis
HPO:Spasticity

2 Interventions

Name: lumbar puncture and blood withdrawal

Description: lumbar puncture performed to detect OCB for diagnostic purposes and blood withdrawal for SNP screening
Type: Procedure
Group Labels: 2

control subjects multiple sclerosis patients

Name: Intermittent theta burst stimulation (iTBS) therapeutic protocol for spasticity

Description: iTBS will be delivered over the scalp site corresponding to the leg area of primary motor cortex contralateral to the affected limb. The active motor threshold (AMT) will be defined as the minimum stimulation intensity required to evoke a liminal motor potential from the Soleus muscle during voluntary contraction. The stimulation intensity will be about 80% of AMT. The iTBS stimulation protocol consists of 10 bursts, each burst composed of three stimuli at 50 Hz, repeated at a theta frequency of 5 Hz every 10 s for a total of 600 stimuli (200 s). If no MEP will be detectable from the contralateral leg, the site of stimulation will be determined as symmetrical to the motor hot spot. If no MEP will be detectable even from the contralateral leg the coil will be held tangentially to the scalp with its centre placed 1 cm ahead and 1 cm lateral from CZ (10-20 EEG system). In these cases, stimulation intensity will be set to 50% of the maximum stimulator output.
Type: Procedure
Group Labels: 1

multiple sclerosis patients with spasticity and selected SNPs


Primary Outcomes

Description: Quantification of CSF levels of miR-142-3p by qPCR analysis. Relative quantification will be performed by 2^(-ddCt) method.

Measure: CSF concentration of miR-142-3p

Time: T0 (enrollment); MS patients vs Control subjects

Description: Quantification of CSF inflammatory molecules (TNF, IL-1β, IL-6, IL-17, IFN-γ, IL1ra, IL-22, IL-2, IL-2ra, IL-10, IL-4, IL-5, IL-13, IL-12p40, IL-8) by Luminex multiplex assays; neurofilaments, beta amyloid, tau proteins and growth factors (like NGF, PDGF and BDNF) by Luminex multiplex assays. Data will be expressed as pg/ml.

Measure: CSF concentration of soluble molecules

Time: T0 (enrollment); MS patients vs Control subjects

Description: Clinical disability will be certified by a qualified neurologist through the Progression Index (PI) calculated as EDSS combined with disease duration (EDSS/disease duration). Disease duration is estimated as the number of years from onset to the most recent assessment of disability and EDSS scale ranging from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

Measure: Clinical disability assessment by Progression Index calculation for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: The Multiple Sclerosis Functional Composite (MSFC) is a three-part composite clinical measure. Three variables were recommended as primary measures: Timed 25-Foot walk; 9-Hole Peg Test; and Paced Auditory Serial Addition Test (PASAT- 3"). The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each patient at each time point. There are 3 components: the average scores from the four trials on the 9-HPT; the average scores of two 25-Foot Timed Walk trials; the number correct from the PASAT-3. The scores for these three dimensions are combined to create a single score that can be used to detect change over time. This is done by creating Z-scores for each component. MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0 (Where Zxxx =Z-score) Increased scores represent deterioration in the 9-HPT and the 25-Foot Timed Walk, whereas decreased scores represent deterioration in the PASAT-3.

Measure: Clinical disability assessment by MSFC calculation for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: By conventional MRI (1.5 Tesla) the following parameters will be evaluated: dual-echo proton density, FLAIR, T1-WI, T2-WI, and contrast-enhanced T1-WI after intravenous gadolinium (Gd) infusion (0.2 ml/kg). A new Gd+ lesion is defined as a typical area of hyperintense signal on postcontrast T1-WI. A new or newly enlarging lesion on T2-WI is defined as a rounded or oval lesion arising from an area previously considered as normal appearing brain tissue and/or showing an identifiable increase in size from a previously stable-appearing lesion. An active scan is defined as showing any new, enlarging or recurrent lesion(s) on postcontrast T1- and T2-WI.

Measure: Neuroradiological assessment for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: To assess synaptic excitability by SICI, ICF and LICI, motor thresholds will be calculated at rest as the lowest stimulus intensity able to evoke MEPs of about 50uV in 5 out of 10 consecutive trials (cts), and during a slight voluntary contraction of the target muscle (20-30% of the max voluntary contraction) as the lowest intensity able to evoke MEPs > 100uV in 5 out of 10 cts. The mean peak-to-peak amplitude of the conditioned MEP (cMEP), at each interstimulus interval (ISI), will be expressed as a percentage of the mean peak-to-peak amplitude of the test MEP (tMEP). PAS-induced LTP-like plasticity will be expressed as changes of the average MEPs size at each time point after PAS compared to the average baseline MEPs size. Before PAS, 25 MEPs, evoked by single TMS pulses over the APB motor hot spot set at an intensity to obtain MEPs size of about 1mV peak-to-peak, will be collected. The same stimulus intensity will be used to obtain 25 MEPs 0', 30' and 60' after PAS.

Measure: Neurophysiological assessments for correlation analysis with CSF-miR-142-3p levels

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: To investigate miR-142-3p association with synaptopathy-driven disease progression (measured in terms of clinical or radiological changes and TMS variables), multivariable generalized linear models (GLM) will be applied considering miR level in the CSF as an independent variable adjusting for demographical, clinical, neuroradiological, neurophysiological, biochemical factors and treatments. In the case of unsuccessful identification, Principal Component Analysis (PCA) will be performed to evaluate the miR contribution with other molecules in the CSF (as cytokines, chemokines, growth factors, neurofilaments, beta amyloid and tau protein) to synaptopathy-driven disease progression to reduce the number of variable examined and increase the power of multivariate analysis. Statistical correlations will be repeated on the identified PCA components including miR-142-3p as part of the component. The significance level is established at p<0.05.

Measure: Statistical correlation of miR-142-3p levels in MS CSF with disease and neurophysiological parameters

Time: T0 (enrollment), T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months).

Secondary Outcomes

Description: miR-142-3p levels in the CSF will be assessed at T0, as reported above. The responsiveness to the DMT, who MS patients underwent as part of their clinical routine, will be evaluated according to clinical and neuroradiological parameters considered in the primary outcomes. Changes in such parameters will be evaluated at different time points during a six-year follow-up (T12-T0; T24-T0, T24-T12, etc). Both univariable and multivariable approaches and stratification of patients based on DMT treatment will be performed.The significance level is established at p<0.05.

Measure: Statistical correlation of miR-142-3p levels in MS CSF with patient's responsiveness to disease modifying therapies (DMTs).

Time: Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: Genetic screening will be performed on peripheral blood withdrawn from MS patients at T0. The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed. Univariable and multivariable correlations of minor allele presence of each screened SNP with clinical, neuroradiological and neurophysiological parameters, detected in the primary outcomes (T0, T12, T24, T36, T48, T60, T72), will allow the identification of SNPs relevant to disease progression. The significance level is established at p<0.05.

Measure: Genotyping of SNPs in SLC1A3 and MIR-142 genes for correlation analysis with disease parameters

Time: Time Frame: T0 (enrollment); Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up

Description: Lower limb spasticity will be evaluated in all recruited MS patients at T0 and during 6-year-follow-up. A subgroup of MS patients with lower-limb spastic symptoms and carrying SNPs in in SLC1A3 and MIR-142 genes relevant to disease progression will undergo therapeutic iTBS protocol daily for two weeks (interventional substudy) and spasticity will be assessed also immediately before the beginning (W0) and after 2 weeks at the end of the protocol (W2). The H/M amplitude ratio of the Soleus H reflex will be evaluated by EMG recordings as an index of spinal excitability. Compound motor action potentials (cMAPs) and H reflex will be evoked by electrical stimulation of the tibial nerve. The maximum amplitudes of the H reflex (H) and CMAP (M) potentials will be measured from peak to peak and H/M ratio was calculated by dividing the maximal amplitude of H wave by that of M wave.

Measure: Lower limb spasticity assessment by H/M amplitude ratio for the therapeutic TMS substudy

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Description: Lower limb spasticity will be evaluated in all recruited MS patients at T0 and during 6-year-follow-up. A subgroup of MS patients with lower-limb spastic symptoms and carrying SNPs in in SLC1A3 and MIR-142 genes relevant to disease progression will undergo therapeutic iTBS protocol daily for two weeks (interventional substudy) and spasticity will be assessed also immediately before the beginning (W0) and after 2 weeks at the end of the protocol (W2). The Modified Ashworth Scale (MAS) assesses resistance during passive soft-tissue stretching ranging from 0 to 4 score.

Measure: Lower limb spasticity assessment by MAS score for the therapeutic TMS substudy

Time: Changes from T0 (enrollment) to T12 (12 months), T24 (24 months), T36 (36 months), T48 (48 months), T60 (60 months) and T72 (72 months) of follow-up; Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Description: Minor allele presence of each screened SNP in SLC1A3 and MIR-142, identified at T0 as relevant to disease progression (see above), will be correlated with changes in spasticity parameters (the H/M amplitude ratio of the Soleus H reflex and MAS score) upon the iTBS treatment (W2-W0). The significance level is established at p<0.05.

Measure: Statistical correlation of response to iTBS treatment with MS-significant SNPs of both SLC1A3 and MIR-142.

Time: T0 (enrollment); Changes from the starting day (W0) to the end of the 2-week iTBS protocol (W2).

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There are 18 SNPs

SNPs


1 rs1049522

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


2 rs1049524

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


3 rs137852620

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


4 rs2032892

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


5 rs2269272

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


6 rs2269273

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


7 rs2562582

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


8 rs2731886

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


9 rs377637047

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


10 rs4869675

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


11 rs4869676

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


12 rs529802001

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


13 rs544684689

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


14 rs547987105

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


15 rs549927573

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


16 rs550842646

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


17 rs562696473

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.


18 rs573562920

The following SNPs in MIR142 gene coding for miR-142-3p: rs550842646, rs377637047, rs562696473, rs529802001, rs547987105, rs573562920, rs544684689 and rs549927573, and in SLC1A3 gene coding for GLAST/EAAT1: rs137852620, rs2032892, rs2562582, rs4869675, rs4869676, rs2269272, rs2269273, rs1049522, rs1049524 and rs2731886, will be analyzed.



HPO Nodes


HPO:
HP:0001257: Spasticity
Genes 1081
NDUFS7 CTC1 SPG11 FA2H SARS1 PYCR2 AP1S2 SYNJ1 FMN2 DNAJC6 ERCC4 PYCR2 ENTPD1 UBAP1 DARS1 REPS1 ARX OTUD6B FAR1 POLG KCNB1 NIPA1 ARL6IP1 SIX6 SPART CNTNAP2 PIGC LIPT1 RAB3GAP2 ZC3H14 MTFMT BSCL2 TUBB3 CPT1C NDUFV2 LINGO1 RANBP2 GM2A SETBP1 KY PPARGC1A PEX10 GCDH PLP1 GBA CTNNB1 B3GALNT2 RPIA NEFL TACO1 DDHD1 CYB5R3 DYNC1I2 NDST1 ALDH18A1 CSF1R ANK3 KIF1C TRNK DCPS NR2F1 VCP ATP6 B4GALNT1 MAPK8IP3 SAMHD1 SLC6A5 NDUFA6 HSPD1 GPAA1 UBQLN2 GJC2 VAMP1 ATP2B3 ATXN3 SDHA NDUFS3 MATR3 C12ORF4 GLYCTK ND3 TBC1D23 SPART STAMBP CKAP2L BCL11B SLC30A10 PLA2G6 CC2D1A DNM1 SOX10 LMX1B NDUFB8 RPGRIP1L ATXN3 GABRB2 ADAM22 NTRK2 CLP1 DARS2 MYO5A ERLIN2 KANK1 FIG4 TIMM8A FRMPD4 DNMT1 WASHC4 TTR USP8 DDX3X PSAT1 PEX7 GRIN1 CYB5A SLC2A1 DHDDS AP5Z1 CCT5 NUP62 ARSI PIGN TYROBP NAGA NUBPL THOC2 MFF HCN1 WDR48 GLRX5 SDHA SDHB ZC4H2 EZH2 MRPS22 ATP13A2 ACAT1 WARS2 PHACTR1 GBA2 AP4E1 VPS11 NDUFA12 RTN2 ECHS1 ITM2B B4GAT1 MED25 APC NDUFV2 TIMM50 SOX4 MAN2B1 ERCC3 ADAT3 FAR1 PSAP CRADD ARX SZT2 CYP7B1 TUFM ASPA AFG3L2 TREM2 POLR3A SLC1A4 SPG7 NPC1 L1CAM CNPY3 STXBP1 GJB1 MAN1B1 STXBP1 SNORD118 NDUFS2 CYP2U1 COL4A2 WDR73 MAG SMPD1 YWHAG DCTN1 NDUFAF6 TAF15 COPB2 EXOSC3 SDHA PIGP ATAD3A FTL DNAJC6 UBA5 ADAT3 TELO2 PEX26 SUCLA2 NUS1 CASK ALDH18A1 MARS2 AFG3L2 SLC19A3 REEP1 PLCB1 PSAT1 ERLIN2 TARDBP AIFM1 ERCC4 CARS2 SYNJ1 BCOR NSUN2 DSTYK PANK2 STXBP1 DDX3X TRAPPC12 TOE1 SERAC1 TECR LMAN2L CACNA1G DDHD2 L1CAM PIGA KCNJ6 CYFIP2 CIT GJC2 PFN1 PPP1R15B PHGDH PGAP1 NADK2 GAD1 TRNL1 ATP13A2 TAF2 ATM STUB1 NDUFA10 SOD1 RSRC1 CYP27A1 GABRA2 TRNI NEFH KCNA1 PRDM8 ACTL6B SLC19A3 NEK1 CTSD NDUFS1 SLC18A2 ALDH18A1 DNAJC19 PAX3 TRAK1 RAB18 ERLIN1 CLTC L2HGDH PEX6 TUBB4A FOXG1 TSEN54 PPP3CA GLRA1 COASY CACNA1E PSEN1 NDUFAF3 MECP2 DNMT1 FUS GPT2 OPA1 CYB5R3 AFG3L2 ADD3 TBC1D20 CRLF1 LMNB1 ATRX SCO2 PSAP KIF5A PEX2 CTNNA2 ND4 ELOVL4 RNASEH2B UCHL1 NDUFA9 UFC1 TSEN15 B4GALNT1 WASHC5 TMEM67 GSS SLC25A22 GRIN2B EPRS1 SCN2A PEX16 TARDBP MFSD2A TYROBP IKBKG SIL1 MRPS34 EIF2S3 CSF1R ARSA KIF11 SLC39A14 SDHA DHCR24 HSPD1 ARX ATRX FUCA1 OCLN NDE1 TPI1 AMPD2 DENND5A CLPB FOXRED1 MECP2 PHGDH SLC2A1 TUBA1A C19ORF12 GLRX5 ZFYVE27 GABRB2 AP5Z1 TBCD ARNT2 TRNF POMGNT1 CLIP2 HTRA2 GBA2 PLA2G6 SIK1 GRIK2 CHP1 DARS2 NKX6-2 MECP2 GFM1 PPP1R15B CFAP410 AARS2 TBCE UNC80 WDR4 AP4S1 ATXN8 ARX HTRA1 TOE1 PDHX ADAR HTT GTF2E2 CASK TRIT1 ATAD1 AP4S1 HEPACAM GALC MED13L RFT1 PNP GRM1 IDUA RETREG1 KCNA2 SLC52A2 SLC1A2 AP1S2 COL4A1 FDX2 KDM5B FLNA ATRX AGTPBP1 WDR45B MTPAP NDUFA13 NTNG1 PGAP1 GTF2H5 SON TARS1 ATP6V1A POLR1C EIF2B3 TMEM231 SDHAF1 AIMP1 ROGDI BSCL2 FBXO7 NIPA1 UBA5 ABCD1 LIPT2 HPRT1 FA2H COASY PEX13 AMPD2 MPLKIP HLA-DQB1 NACC1 NALCN RARS2 PPP3CA ARG1 DCX PDHA1 GBE1 AP4E1 ND5 NUP214 ARX TPRKB L1CAM OTUD6B GJA1 GTF2I KCNT1 PEX1 PEX6 FA2H AP4B1 SLC17A5 ATXN8OS BCS1L SYNGAP1 NEFH FGFR1 OPA1 ARX DAO ATXN7 GPAA1 PNPLA6 CRBN RNU4ATAC CASK ATP6 AP3B2 VPS11 ERLIN1 KIDINS220 ATXN3 TXN2 GUF1 KIF1A TRMT10A MCCC2 ATP6AP2 ISCA1 TANGO2 ITM2B CHCHD10 ATXN8OS VWA3B RNASEH2A FRRS1L SLC13A5 SIGMAR1 WWOX MRE11 GATAD2B ATP6V1A HNRNPA1 ERLIN2 SDHAF1 VAMP1 OSGEP CAMK2A ATP6V0A2 COLGALT1 DSTYK PARS2 DDHD2 LIPT1 PON2 WWOX NTRK2 SUZ12 RTTN ELP2 PEX16 TELO2 RUSC2 GRIN1 ARX TNIK ADAR GRIN2B SPG11 OPA3 GABBR2 SURF1 CLPB TPK1 ARSA WDR62 RERE NECAP1 WWOX EED ERCC5 MACF1 ACER3 CYFIP2 PEX5 SPG7 ATP7A PLA2G6 RNASEH2C KIF5A HLA-DRB1 ALS2 MAPT REEP2 SLC2A1 OPTN SPG11 FGF12 ARX NOTCH3 SLC33A1 SOX10 ATP6AP2 MCOLN1 RAB27A ERCC6 GFM2 L2HGDH SOD1 BSCL2 PLAA CNTNAP1 KCNJ6 SCYL1 POLR3A SACS SLC2A1 VPS13C UFM1 KCNA2 C12ORF65 HSD17B10 SURF1 SQSTM1 EXOSC8 PEX19 FTL EIF2B4 TTC19 POLA1 MCCC1 LYRM7 SCN1B SETBP1 MED17 MTPAP PEX3 RARS1 NEUROD2 INPP5K RANBP2 ZFYVE26 ERCC5 CLCN4 NDE1 ABHD12 FBXO7 C12ORF65 STN1 GDAP2 GNAO1 STUB1 MOCS1 FUS RARS1 EPM2A PODXL RNASEH2A RNASET2 MARS2 C19ORF12 PARS2 UCHL1 CACNA1A PMPCA HMGCL DHCR24 KIF1A CYP2U1 PRNP SIL1 WDR26 CACNA1G CACNA1D ATP6 SNCA VPS53 CCT5 TRIM8 KCNA1 PHGDH PQBP1 HPRT1 GABRA5 ARL6IP1 ATXN3 REEP1 RAB18 PARK7 SCYL1 RTTN NDUFAF5 CACNA1G GAN AMACR CPT1C CHMP2B LAMB1 NDUFS2 ATP13A2 ALDH3A2 AARS1 PRRT2 IBA57 FARS2 PIGQ FBXO31 KLC2 KCNA1 KMT2B PNPLA6 TP53RK PLP1 SOX2 ATXN2 SLC2A3 ASPA TMTC3 TIMM50 ERCC2 WDR73 TRAPPC12 METTL23 STXBP1 NKX6-2 SPG21 ND1 GRIA3 HACE1 FXN NACC1 SPAST SPATA5 SPG21 NDUFAF4 ND6 GBA UBTF AUH ND2 RPS6KA3 ACP5 GJA1 TUBB3 PRPS1 GBA ALDH3A2 ATXN8 CAPN1 DLD NT5C2 TSEN2 MTFMT NAA10 TRMT5 SELENOI ANKLE2 GBA L1CAM RNF113A HMGCL KDM5C ANG UNC80 RAB3GAP2 CLP1 GBE1 VCP FRRS1L DHPS SEPSECS ABCC8 FUCA1 TFG SACS MOCS2 PEX14 KIF2A WARS2 CAPN1 PTS IREB2 TREX1 MED25 XPA SLC2A1 GLB1 TCTN2 NSUN2 CNKSR2 ATXN1 LMNB1 ELN PON1 ERCC5 UBTF TECPR2 MECR MFN2 CYP27A1 PSAP COX10 COX15 XPC ARV1 OPA1 SIGMAR1 L1CAM FLRT1 ARX PET100 PAX3 CACNA1D ERCC2 PRPH MBOAT7 BEAN1 TRNV CTNNB1 PANK2 TREM2 AARS1 TREX1 STXBP1 PMPCB RFC2 ERCC3 PRDM8 BCL11B INPP5K CHMP1A HTT NDUFV1 ZNF592 SCN2A BCS1L SYNE1 KRAS C9ORF72 EZR ALDH18A1 SLC25A22 PPT1 KIF1A PEX3 COX15 ZNF335 GLT8D1 JAM3 ZFR SDHD TRNW ANG PQBP1 GLE1 PFN1 SLC2A1 NUS1 OPA1 PRPH GAN ATL1 MICOS13 NAGA PUM1 CDKL5 MARS1 IRF2BPL TRAK1 IDUA HACE1 ALS2 L1CAM SUMF1 REEP2 CNOT1 PDCD1 SLC30A10 TAF2 GM2A MCCC2 GLRB NT5C2 PRKN KIF1C FARS2 ST3GAL3 OSTM1 LIMK1 SNCA ZFYVE26 SPTAN1 TBL2 ENTPD1 ATL1 ARF1 NADK2 SLC1A2 TBP POLR3B PNPLA6 KATNB1 AP4M1 TAF1 MTO1 PCDH12 CYP7B1 DNM1L HEPACAM KCNQ2 XPA ALG11 CLIC2 CLIC2 MICOS13 ATXN10 AUH ACP2 NDUFAF2 GNAO1 ISCA2 SLC6A8 IFIH1 CCDC88C ARSA EXOSC9 GJC2 COG2 SURF1 IBA57 SNX14 LAGE3 KCNA4 SYNE1 HSPD1 ATXN2 PSAP GRIA4 UNC13A TBK1 TBCE OCLN GPT2 RAD50 TRAPPC9 ERCC3 RAB11B GTPBP2 PLA2G6 RAB3GAP2 EIF2B2 TBC1D20 LIAS SPG11 ASNS MED23 SETX WDR45 CCDC88C POLR3B VAPB AFG3L2 ERCC2 AUTS2 ATAD3A TFG CCNF RLIM MECP2 SLC35A2 PANK2 TAF1 SLC1A4 UBA5 C12ORF65 GBA2 ALS2 C19ORF12 ALS2 EDNRB WDR45 KIF5C MECP2 ERCC2 SLC2A1 SCN3A OPA3 ADSL BICD2 DDHD1 GCDH ERBB4 NARS2 TRNL1 EEF1A2 AP4B1 EDC3 COG2 NDUFS4 SLC25A15 SPR SLC13A5 CC2D2A VPS37A MED25 CACNA1B ALS2 RAB3GAP1 SCN1B GRIN2D DDB2 LINS1 PAFAH1B1 PLP1 DEGS1 NPC2 BSCL2 TRNP NDUFAF5 ATP6V1A SLC45A1 SPG7 TCF20 EIF2B5 SNX14 RNASEH2B NALCN PRSS12 PEX11B VPS13C COA8 CLCN4 EIF2B1 HSD17B4 DYNC1H1 PNP NDUFS4 DCTN1 MCCC1 EZH2 WASHC4 POLR3A CDKL5 VPS13D PCLO NUP62 WASHC5 ARG1 AGA BCOR RNASEH2C GFAP GPHN NDUFA4 NDUFA13 NSD1 LRRK2 KLC2 NDUFA2 CLIP1 DHDDS SLC16A2 ARSA RTN2 MTHFS PON3 SLC25A12 SPAST PNPLA8 EARS2 SAMHD1 TRNK IKBKG AP4M1 ANK3 SLC33A1 MAG PRUNE1 TUBG1 GABRG2 AIMP1 BAZ1B HNMT SLC25A15 SCN8A IBA57 PINK1 KDM5C RAB3GAP1 ELOVL4 TUSC3 NDUFS8 PRNP SLC13A5 IARS1 EXTL3 AMPD2 HIKESHI BOLA3 ECHS1 OPHN1 PGAP1 ALDH18A1 EPHA4 SPTBN2 ROGDI SPTBN2 IQSEC1 PNPLA6 GPHN NEXMIF TRNW ALG11 KIDINS220 PANK2 TDP1 PNKP SLC39A14 FOXP1 HUWE1 SCN3A TBCD ANXA11 ALS2 C19ORF12 NHLRC1 TSEN54 EML1 MECP2 GTF2IRD1 MLC1 PEX12 SDHD FBLN1 ATP6V1E1 IFIH1 CLTC SPATA5
Protein Mutations 0