Publications by authors named "Mehdi Khorrami"

15 Publications

  • Page 1 of 1

Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population.

Sci Rep 2021 Apr 8;11(1):7713. Epub 2021 Apr 8.

Isfahan Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Alterations in the regulatory mechanisms that control the process of myelination in the nervous system, may lead to the impaired myelination in the Multiple sclerosis. The Hippo pathway is an important mediator of myelination in the nervous system and might contribute to the pathophysiology of MS. This study examined via qPCR the RNA expression of YAP1, TAZ, and CRB3 as the key effectors of the Hippo pathway and also, VDR in the peripheral blood of 35 sporadic, 37 familial MS patients; and also 34 healthy first-degree relatives of the familial MS patients (HFR) and 40 healthy individuals without a family history of the disease (control). The results showed the increased expression of VDR in the sporadic group, as compared to other groups. There was also an increased expression of TAZ in the familial and HFR groups, as compared to the control group. The familial and sporadic patients displayed a significantly lower level of expression of YAP1 in comparison to the HFR group. The increased expression level in the sporadic patients and control group, as compared to the HFR group, was seen in CRB3. We also assessed different clinical parameters and MRI characteristics of the patients. Overall, these findings suggest that Hippo pathway effectors and also VDR gene may play a potential role in the pathophysiology of the sporadic and familial forms of MS. Confirmation of different gene expression patterns in sporadic and familial MS groups may have obvious implications for the personalization of therapies in the disease.
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http://dx.doi.org/10.1038/s41598-021-87131-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032816PMC
April 2021

Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature.

J Hum Genet 2021 Mar 25. Epub 2021 Mar 25.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

In recent years, the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia, named spastic paraplegia type 57 (SPG57). Until now, four pathogenic homozygous variants of the TFG gene have been reported associated with SPG57. Two consanguineous Iranian families (1 and 2), the first one with two affected members and the second one with one, all with an early-onset progressive muscle weakness, spasticity, and several neurological symptoms were examined via the whole-exome sequencing. Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) have been found in the related families. The candidate variants were confirmed by Sanger sequencing and found to co-segregate with the disease in families. The bioinformatics analysis showed the deleterious effects of these nucleotide changes and the variants were classified as pathogenic according to ACMG guidelines. A comparison of the clinical presentation of the patients harboring c.41A>G (p.Lys14Arg) with previously reported SPG57 revealed variability in the severity state and unreported clinical presentation, including, facial atrophy, nystagmus, hyperelastic skin, cryptorchidism, hirsutism, kyphoscoliosis, and pectus excavatum. The affected member of the second family carried a previously reported homozygous c.316C>T (p.Arg106Cys) variant and displayed a complex HSP including optic atrophy. Remarkable clinical differences were observed between the family 1 and 2 harboring the c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) variants, which could be attributed to the distinct affected domains (PB1 domains and coiled-coil domains), and therefore, SPG57 might have been representing phenotype vs. variant position correlation.
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http://dx.doi.org/10.1038/s10038-021-00919-9DOI Listing
March 2021

Identification of a Missense Variant in the EIF2B3 Gene Causing Vanishing White Matter Disease with Antenatal-Onset but Mild Symptoms and Long-Term Survival.

J Mol Neurosci 2021 Mar 9. Epub 2021 Mar 9.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Vanishing white matter disease (VWM) is a rare autosomal recessive leukodystrophy caused by a mutation in any of the five gene encoding subunits of the translation initiation factors eIF2B1 to eIF2B5. Whole-exome sequencing was performed on a 7-year-old boy with prenatal symptoms, including intrauterine-growth retardation, decreased movements, and oligohydramnios as well as mild intellectual disability, optic atrophy, macrocephaly, mild ataxia, and white matter lesions after birth. Analysis of WES data revealed a homozygous missense variant, c.C590T (p.Thr197Met) in the EIF2B3 gene (NM_0203650). The candidate variant was confirmed by Sanger sequencing and found to co-segregate with disease in family members. Pathogenicity analysis, 3D protein modeling, and stability assessment showed the deleterious effects of this nucleotide change. Previous studies suggest a direct relationship between the onset of symptoms and the progression rate and severity of the disease. All described cases of EIF2B deficiency with antenatal-onset led prenatal death; if they were born, they experienced clinical exacerbation, seizure, severe encephalopathy, and consequent infantile death (< 1 year). The patient of this study had never had seizure, which could be a potential explanation for the observed mild clinical picture, chronic state, and long-term survival until the age of seven. This study reported the first VWM due to EIF2B gene deficiency with antenatal-onset but mild symptoms and long-term survival. The result of this study showed that stressor factors, particularly seizure, could have a substantial role in poor prognosis and early neonatal death.
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http://dx.doi.org/10.1007/s12031-021-01810-0DOI Listing
March 2021

An interdependence between GAPVD1 gene polymorphism, expression level and response to interferon beta in patients with multiple sclerosis.

J Neuroimmunol 2021 Apr 30;353:577507. Epub 2021 Jan 30.

Department of Medical Genetics, Faculty of Medicine, Tabriz university of Medical Sciences, Tabriz, Iran. Electronic address:

Interferon-β (IFN-β) is among the first drugs used for reducing the symptoms of multiple sclerosis (MS). Many studies show that the genetic predisposition of patients might modulate their response to IFN-β treatment. In this study GAPVD1 gene expression and the genotyping of rs2291858 variant were analysed in 100 responder and 100 non-responder patients with MS treated using IFN-β. Moreover, rs2291858 genotyping was performed for 200 patients with MS and 200 healthy controls. GAPVD1 expression was significantly increased in the responder patients than in non-responders and the distribution of rs2291858 polymorphism was significantly different between them. The GAPVD1 expression level in AA genotype of the responder group was higher than that in other genotypes of these two groups. The results show that the GAPVD1 expression level and rs2291858 genotype probably affect the response to IFN- β in patients with MS.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577507DOI Listing
April 2021

Connection of miR-185 and miR-320a expression levels with response to interferon-beta in multiple sclerosis patients.

Mult Scler Relat Disord 2020 Sep 8;44:102264. Epub 2020 Jun 8.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by neurodegeneration in the CNS. Interferon-beta (IFN-β) is an FDA-approved drug used as the first-line treatment for relapse-remitting multiple sclerosis (RRMS). The exact mechanism of IFN-β during the treatment of RRMS still remains unknown. Recently, many studies have shifted towards the role of miRNAs in the treatment of MS patients.

Methods: Herein, the expression level of miR-185-5p and miR-320a has been evaluated in order to candidate them as novel biomarkers for monitoring the response to IFN-β therapy. For this purpose, one-hundred whole blood samples from patients with RRMS were collected, consisting of 50 responders and 50 non-responders to IFN-β therapy. To predict the possible molecular mechanisms of IFN-β and highlight the role of these miRNAs, in silico analysis was applied to enrich the signaling pathways which may be involved based on the target genes of miR-185-5p and miR-320a.

Results: It is identified that the differentially expressed miR-185-5p was statistically significant between the two treated groups with IFN-β. Furthermore, MAPK signaling pathway was suggested as the main non-canonical pathway involved in IFN-β therapy.

Conclusion: miR-185-5p could be considered as a novel biomarker for monitoring the response to IFN-β therapy.
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http://dx.doi.org/10.1016/j.msard.2020.102264DOI Listing
September 2020

miR-504 expression level is increased in multiple sclerosis patients responder to interferon-beta.

J Neuroimmunol 2020 Mar 7;342:577212. Epub 2020 Mar 7.

Immunology research center, Tabriz University of medical science, Tabriz, Iran. Electronic address:

Multiple sclerosis is immune-mediated disease of the central nervous system characterized by demyelination in axons. IFN-β is first-line treatment of MS. Biomarkers are needed for early prediction of responders and non-responders to therapy in the first month of treatment to avoid further disabilities. In this study, we analyzed the expression level of miR-504 and miR-711 in 52 IFN-β responder patients in comparison to 53 non-responders. In the next step, the in-silico analysis was used to enrich related signaling pathways. The expression level of miR-504 was significantly higher in patients who respond to IFN-β therapy, compared with non-responders and we obtain related statistically significant KEGG molecular signaling pathways. Our findings suggest that miR-504 can be considered as a novel biomarker for response to IFN-b therapy.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577212DOI Listing
March 2020

A Novel Pathogenic Variant in NAGLU (N-Acetyl-Alpha-Glucosaminidase) gene Identified by Targeted Next-Generation Sequencing Followed by in Silico Analysis.

Iran J Child Neurol 2019 ;13(4):173-183

Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Mucopolysaccharidosis IIIB (MPS IIIB) (Sanfilippo Syndrome Type B; OMIM 252920) is an autosomal recessive metabolic disorder caused by mutations in the gene which encode lysosomal enzyme N-acetyl-glucosaminidase, involved in degradation of complex polysaccharide, heparan sulfate. The disease is characterized by progressive cognitive decline and behavioral difficulties and motor function retardation.

Materials & Methods: In this study, targeted exome sequencing was used in consanguineous parent (mother) of a deceased child with clinical diagnosis of mucopolysaccharidosis. Sanger sequencing was performed to confirm the candidate pathogenic variants in extended family members and segregation analysis. In silico pathogenicity assessment of detected variant using multiple computational predictive tools were performed. Computational docking using the Molegro Virtual Docker (MVD) 6.0.1 software applied to evaluate affinity binding of altered protein for its ligand, N-Acetyl-D-Glucosamine. Moreover, with I-TASSER software functional alterations between wild and mutant proteins evaluated.

Results: We identified a novel heterozygote deletion variant (c.1294-1304 del CTCTTCCCCAA, p.432LeufsX25) in the gene. The variant was classified as pathogenic based on the American College of Medical Genetics and Genomics guideline. Computational docking with the Molegro Virtual Docker (MVD) 6.0.1 software confirmed different affinity binding of truncated protein for its ligand. Moreover, I-TASSER software revealed structural and functional alterations of mutant proteins.

Conclusion: This study expands the spectrum of pathogenic variants and confirms the utility of targeted NGS sequencing in genetic diagnosis and also the utility and power of additional family information.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789092PMC
January 2019

Toward Noise Certification during Design: Airframe Noise Simulations for Full-Scale, Complete Aircraft.

CEAS Aeronaut J 2019 Mar 16;10(1):31-67. Epub 2019 Mar 16.

Exa GmbH, Curiestrasse 4, D-70563 Stuttgart, Germany.

An overview of a recent, NASA-sponsored effort to substantially advance simulation-based airframe noise prediction is presented. An accurate characterization of this component of aircraft noise requires a high-fidelity representation of the finer geometrical details associated with the landing gear and wing high-lift devices, such as slats and flaps, which constitute major noise sources. To achieve this ambitious goal, a systematic approach was followed to extend our current state-of-the-art computational tools to a full-scale, complete aircraft in landing configuration within a realistic flight environment. The work involved several phases: high-fidelity, large-scale, unsteady flow simulations; model-scale experiments in ground-based facilities; and farfield noise prediction for a full-scale, complete aircraft. The comprehensive aeroacoustic database generated during the course of the effort provided a wealth of relevant information for full validation and benchmarking of the advanced computational tools used in the present work. The database will also foster the development of simulation methodologies with improved predictive capabilities.
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http://dx.doi.org/10.1007/s13272-019-00378-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837503PMC
March 2019

Variants in Human Prostacyclin Receptor Gene in Patients with Migraine Headache.

Iran J Psychiatry 2018 Oct;13(4):239-243

Psychiatry and Psychology Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Prostaglandin I2 receptor plays a major physiologic role in the relaxation of arterial smooth muscle and vasodilation and possibly during migraine attacks. Therefore, in this study, the coding and noncoding exons and exon-intron boundaries of Prostaglandin I2 receptor gene were examined in patients with migraine headache and healthy controls and the potential effects of identified single nucleotide variations were evaluated using direct PCR-sequencing and in silico analysis. In this study, the peripheral blood samples of 50 patients and 50 controls were examined to find any mutation in coding and noncoding exons and exon-intron boundaries of PTGIR gene. DNA was extracted and all the samples were amplified by polymerase chain reaction (PCR) and sequenced. In this study, the patients had a mean age of 35.235 ± 10.99 years (range, 9-60 yrs.), and female to male ratio was 4:1 in this group. The controls had a mean age of 35.058 ± 11.116 years (range, 8-59 yrs.), and female to male ratio was 3.7:1.3 in this group. Two patients had mutations in exon 2. The first mutation was located in exon 2 (at amino acid position 251) of PTGIR gene at nucleotide position c.866A > T, a synonymous variant described previously in the database. The second mutation was located in exon 2 c.867G > A, which is a missense variant. Sequence analysis revealed high occurrence of previously reported intronic variants mostly in a homozygous statue. The data supported the hypothesis that mutations in PTGIR gene, particularly the mutation we described, should be considered even in cases of migraine. The presence of this mutation in patients with family history raises important issues regarding genetic counselling.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320380PMC
October 2018

In silico analysis of SLC3A1 and SLC7A9 mutations in Iranian patients with Cystinuria.

Mol Biol Rep 2018 Oct 1;45(5):1165-1173. Epub 2018 Aug 1.

Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran.

Cystinuria is an autosomal recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from renal tubule and small intestine. Mutations in two genes: SLC3A1, encoding the heavy chain rbAT of the renal cystine transport system and SLC7A9, the gene of its light chain b AT have a crucial role in the diseases. In our previous studies from Iranian populations with Cystinuria totally six and eleven novel mutations respectively identified in SLC3A1 and SLC7A9 genes. In this study, we conducted an in silico functional analysis to explore the possible association between these genetic mutations and Cystinuria. MutationTaster, PolyPhen-2, PANTHER, FATHMM. PhDSNP and MutPred was applied to predict the degree of pathogenicity for the missense mutations. Furthermore, Residue Interaction Network (RIN) and Intron variant analyses was performed using Cytoscape and Human Slicing Finder softwares. These genetic variants can provide a better understanding of genotype-phenotype relationships in patients with Cystinuria. In the future, the findings may also facilitate the development of new molecular diagnostic markers for the diseases.
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http://dx.doi.org/10.1007/s11033-018-4269-6DOI Listing
October 2018

Meta-Analysis of the Association between GABA Receptor Polymorphisms and Autism Spectrum Disorder (ASD).

J Mol Neurosci 2018 May 3;65(1):1-9. Epub 2018 May 3.

Mohkam-kar Health Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Previous studies have reported the association of GABA receptor subunits B3, A5, and G3 single-nucleotide polymorphisms (SNPs) in chromosome 15q11-q13 with autism spectrum disorders (ASDs). However, the currently available results are inconsistent. This study aimed to investigate the association between ASD and the GABA receptor SNPs in chromosomal region 15q11-q13. The association was calculated by the overall odds ratio (OR) with a 95% confidence interval (CI). We used sensitivity analyses and the assessment of publication bias in our meta-analysis. Eight independent case-control studies involving 1408 cases and 2846 healthy controls were analyzed, namely, 8 studies for GABRB3 SNPs as well as 4 studies for GABRA5 and GABRG3 polymorphisms. The meta-analysis showed that GABRB3 polymorphisms in general are not significantly associated with autism [OR = 0.846 (95% CI): 0.595-1.201, I = 79.1%]. Further analysis indicated that no associations were found between GABRB3 SNPs and autism on rs2081648 [OR = 0.84 (95% CI) = 0.41-1.72, I = 89.2%] and rs1426217 [OR = 1.13 (95% CI) = 0.64-2.0, I = 83%]. An OR of 0.95 (95% CI) = 0.77-1.17 was reported (I = 0.0%) for GABRA5 SNPs and an OR of 0.96 (95% CI) = 0.24-3.81 was obtained from GABRG3 SNPs (I = 97.8%). This meta-analysis provides strong evidence that different SNPs of GABA receptor B3, A5, and G3 subunit genes located on chromosome 15q11-q13 are not associated with the development of autism spectrum diseases in different ethnic populations. However, in future research, large-scale and high-quality studies are necessary to confirm the results.
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http://dx.doi.org/10.1007/s12031-018-1073-7DOI Listing
May 2018

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

Mol Neurobiol 2018 Apr 13;55(4):3477-3489. Epub 2017 May 13.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.
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http://dx.doi.org/10.1007/s12035-017-0535-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683945PMC
April 2018

Comparison of Computational and Experimental Microphone Array Results for an 18%-Scale Aircraft Model.

Int J Aeroacoust 2017 21;16(4-5):358-381. Epub 2017 Jul 21.

AVEC, Inc Blacksburg, Virginia 24060.

An 18%-scale, semispan model is used as a platform for examining the efficacy of microphone array processing using synthetic data from numerical simulations. Two hybrid RANS/LES codes coupled with Ffowcs Williams-Hawkings solvers are used to calculate 97 microphone signals at the locations of an array employed in the NASA LaRC 14×22 tunnel. Conventional, DAMAS, and CLEAN-SC array processing is applied in an identical fashion to the experimental and computational results for three different configurations involving deploying and retracting the main landing gear and a part-span flap. Despite the short time records of the numerical signals, the beamform maps are able to isolate the noise sources, and the appearance of the DAMAS synthetic array maps is generally better than those from the experimental data. The experimental CLEAN-SC maps are similar in quality to those from the simulations indicating that CLEAN-SC may have less sensitivity to background noise. The spectrum obtained from DAMAS processing of synthetic array data is nearly identical to the spectrum of the center microphone of the array, indicating that for this problem array processing of synthetic data does not improve spectral comparisons with experiment. However, the beamform maps do provide an additional means of comparison that can reveal differences that cannot be ascertained from spectra alone.
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http://dx.doi.org/10.1177/1475472X17718724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662636PMC
July 2017

RIT2 Polymorphisms: Is There a Differential Association?

Mol Neurobiol 2017 04 3;54(3):2234-2240. Epub 2016 Mar 3.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.
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http://dx.doi.org/10.1007/s12035-016-9815-4DOI Listing
April 2017

c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness.

Eur J Med Genet 2016 Feb 7;59(2):65-9. Epub 2016 Jan 7.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.001DOI Listing
February 2016