Publications by authors named "Adriana P Rebelo"

23 Publications

  • Page 1 of 1

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

Nat Genet 2020 05 4;52(5):473-481. Epub 2020 May 4.

Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.
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http://dx.doi.org/10.1038/s41588-020-0615-4DOI Listing
May 2020

Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation.

Clin Genet 2020 03 5;97(3):521-526. Epub 2019 Dec 5.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Dominant mutations in ATP1A1, encoding the alpha-1 isoform of the Na /K -ATPase, have been recently reported to cause an axonal to intermediate type of Charcot-Marie-Tooth disease (ie, CMT2DD) and a syndrome with hypomagnesemia, intractable seizures and severe intellectual disability. Here, we describe the first case of hereditary spastic paraplegia (HSP) caused by a novel de novo (p.L337P) variant in ATP1A1. We provide evidence for the causative role of this variant with functional and homology modeling studies. This finding expands the phenotypic spectrum of the ATP1A1-related disorders, adds a piece to the larger genetic puzzle of HSP, and increases knowledge on the molecular mechanisms underlying inherited axonopathies (ie, CMT and HSP).
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http://dx.doi.org/10.1111/cge.13668DOI Listing
March 2020

Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy.

Neurol Genet 2019 Apr 1;5(2):e322. Epub 2019 Apr 1.

Department of Neuromuscular Diseases (A.H., A.C., M.G.H., M.M.R.), UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Department of Molecular Neuroscience (A.M.P., H.H.), UCL Queen Square Institute of Neurology; Department of Neuro-ophthalmology (F.B.F.R.C.O.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Division of Neuropathology (Z.J., S.B.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Department of Clinical and Movement Neurosciences (Z.J.), UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Neurology (L.D., S.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Human Genetics and Hussman Institute for Human Genomics (A.P.R., S.Z.), University of Miami, FL; Department of Neurogenetics (C.E.W., J.M.P.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Neurometabolic Unit (I.P.H.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; and Department of Neurodegenerative Disease (S.B.), UCL Queen Square Institute of Neurology, London, United Kingdom.

Objective: To characterize the phenotype in individuals with -related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN).

Methods: Two probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands.

Results: The main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in .

Conclusions: A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.
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http://dx.doi.org/10.1212/NXG.0000000000000322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501639PMC
April 2019

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

J Neuromuscul Dis 2019 ;6(2):201-211

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.

Objective: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.

Methods: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.

Results: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014).

Conclusions: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
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http://dx.doi.org/10.3233/JND-190377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597974PMC
December 2019

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.

Am J Hum Genet 2019 04 28;104(4):767-773. Epub 2019 Mar 28.

Persian BayanGene Research and Training Center, Shiraz, Iran; Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA. Electronic address:

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451742PMC
April 2019

POLG mutations presenting as Charcot-Marie-Tooth disease.

J Peripher Nerv Syst 2019 06 10;24(2):213-218. Epub 2019 Apr 10.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot-Marie-Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.
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http://dx.doi.org/10.1111/jns.12313DOI Listing
June 2019

Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A.

Ann Neurol 2019 03;85(3):316-330

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL.

Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22.

Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.

Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.

Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.
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http://dx.doi.org/10.1002/ana.25426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263419PMC
March 2019

Identification of a new SYT2 variant validates an unusual distal motor neuropathy phenotype.

Neurol Genet 2018 Dec 22;4(6):e282. Epub 2018 Oct 22.

Department of Neurology (N.I.M.-C., M.C., C.V., M.A.S.), University of Miami Miller School of Medicine FL; Department of Biology (Z.G., J.T.L.) and Department of Brain and Cognitive Sciences (Z.G., J.T.L.), The Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge; and Department of Human Genetics (S.C., A.P.R., L.A., S.Z., M.A.S.), Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.

Objective: To report a new missense mutation causing distal hereditary motor neuropathy and presynaptic neuromuscular junction (NMJ) transmission dysfunction.

Methods: We report a multigenerational family with a new missense mutation, c. 1112T>A (p. Ile371Lys), in the C2B domain of , describe the clinical and electrophysiologic phenotype associated with this variant, and validate its pathogenicity in a model.

Results: Both proband and her mother present a similar clinical phenotype characterized by a slowly progressive, predominantly motor neuropathy and clear evidence of presynaptic NMJ dysfunction on nerve conduction studies. Validation of this new variant was accomplished by characterization of the mutation homologous to the human c. 1112T>A variant in , confirming its dominant-negative effect on neurotransmitter release.

Conclusions: This report provides further confirmation of the role of SYT2 in human disease and corroborates the resultant unique clinical phenotype consistent with heriditary distal motor neuropathy. SYT2-related motor neuropathy is a rare disease but should be suspected in patients presenting with a combination of presynaptic NMJ dysfunction (resembling Lambert-Eaton myasthenic syndrome) and a predominantly motor neuropathy, especially in the context of a positive family history.
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http://dx.doi.org/10.1212/NXG.0000000000000282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244021PMC
December 2018

Insights into the genotype-phenotype correlation and molecular function of SLC25A46.

Hum Mutat 2018 12 17;39(12):1995-2007. Epub 2018 Sep 17.

John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.

Recessive SLC25A46 mutations cause a spectrum of neurodegenerative disorders with optic atrophy as a core feature. We report a patient with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy, who is on the mildest end of the phenotypic spectrum. By studying seven different nontruncating mutations, we found that the stability of the SLC25A46 protein inversely correlates with the severity of the disease and the patient's variant does not markedly destabilize the protein. SLC25A46 belongs to the mitochondrial transporter family, but it is not known to have transport function. Apart from this possible function, SLC25A46 forms molecular complexes with proteins involved in mitochondrial dynamics and cristae remodeling. We demonstrate that the patient's mutation directly affects the SLC25A46 interaction with MIC60. Furthermore, we mapped all of the reported substitutions in the protein onto a 3D model and found that half of them fall outside of the signature carrier motifs associated with transport function. We thus suggest that there are two distinct molecular mechanisms in SLC25A46-associated pathogenesis, one that destabilizes the protein while the other alters the molecular interactions of the protein. These results have the potential to inform clinical prognosis of such patients and indicate a pathway to drug target development.
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http://dx.doi.org/10.1002/humu.23639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240357PMC
December 2018

The human motor neuron axonal transcriptome is enriched for transcripts related to mitochondrial function and microtubule-based axonal transport.

Exp Neurol 2018 09 20;307:155-163. Epub 2018 Jun 20.

Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Local axonal translation of specific mRNA species plays an important role in axon maintenance, plasticity during development and recovery from injury. Recently, disrupted axonal mRNA transport and translation have been linked to neurodegenerative disorders. To identify mRNA species that are actively transported to axons and play an important role in axonal physiology, we mapped the axonal transcriptome of human induced pluripotent stem cell (iPSC)-derived motor neurons using permeable inserts to obtain large amounts of enriched axonal material for RNA isolation and sequencing. Motor neurons from healthy subjects were used to determine differences in gene expression profiles between neuronal somatodendritic and axonal compartments. Our results demonstrate that several transcripts were enriched in either the axon or neuronal bodies. Gene ontology analysis demonstrated enrichment in the axonal compartment for transcripts associated with mitochondrial electron transport, microtubule-based axonal transport and ER-associated protein catabolism. These results suggest that local translation of mRNAs is required to meet the high-energy demand of axons and to support microtubule-based axonal transport. Interestingly, several transcripts related to human genetic disorders associated with axonal degeneration (inherited axonopathies) were identified among the mRNA species enriched in motor axons.
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http://dx.doi.org/10.1016/j.expneurol.2018.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713456PMC
September 2018

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.

Am J Hum Genet 2018 03;102(3):505-514

Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na,K-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na,K pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.
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http://dx.doi.org/10.1016/j.ajhg.2018.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985288PMC
March 2018

SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency.

Brain 2018 03;141(3):662-672

Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA.

Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.
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http://dx.doi.org/10.1093/brain/awx369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837310PMC
March 2018

Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease.

J Neurol Neurosurg Psychiatry 2018 03 28;89(3):313-315. Epub 2017 Jul 28.

Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.

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http://dx.doi.org/10.1136/jnnp-2017-315929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152909PMC
March 2018

Novel mutations in provide clues to the pathomechanisms of HSAN-VI.

Neurology 2017 May 3;88(22):2132-2140. Epub 2017 May 3.

From the Departments of Neurosciences, Reproductive Sciences, and Odontostomatology (F.M., C.P., S.T., L.S.) and Department of Molecular Medicine and Medical Biotechnologies (S. Parisi, S. Paladino, T.R.), University of Naples "Federico II"; Neurology Department (M.N., V.P.), "Salvatore Maugeri" Foundation IRCCS-Medical Center of Telese, Telese Terme, Italy; Department of Human Genetics and Hussman Institute for Human Genomics (F.T., A.P.R., S.Z.), Miller School of Medicine, University of Miami, FL; Molecular Medicine Laboratory (C.N., F.M.S.), Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy; and Department of Neurology (M.E.S.), University of Iowa Carver College of Medicine, Iowa City.

Objective: To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin () gene and to evaluate their effect on neurons derived from induced pluripotent stem cells (iPSC).

Methods: The family consisted of 3 affected siblings from nonconsanguineous healthy parents. All members underwent clinical and electrophysiologic evaluation and genetic analysis. Two patients underwent quantitative sensory testing (QST), cardiovascular reflexes, dynamic sweat test, and skin biopsy to evaluate somatic and autonomic cutaneous innervation and to get fibroblast cultures for developing iPSC-derived neurons.

Results: Onset occurred in the first decade, with painless and progressive mutilating distal ulcerations leading to amputation and joint deformity. Sensation to pain, touch, and vibration was reduced. Autonomic disturbances included hypohidrosis, pupillary abnormalities, and gastrointestinal and sexual dysfunction. Nerve conduction studies showed a severe axonal sensory neuropathy. QST and autonomic functional studies were abnormal. Skin biopsy revealed a lack of sensory and autonomic nerve fibers. Genetic analysis revealed 2 pathogenic mutations in the gene affecting exclusively the DST neuronal isoform-a2. Neurons derived from iPSC showed absence or very low levels of DST protein and short and dystrophic neuritis or no projections at all.

Conclusions: Unlike the previous HSAN-VI family, our description indicates that mutations may be associated with a nonlethal and nonsyndromic phenotype. Neuronal loss affects large and small sensory nerve fibers as well as autonomic ones. Induced-PSC findings suggest that dystonin defect might alter proper development of the peripheral nerves. Dystonin-a2 plays a major role in the HSAN-VI phenotype.
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http://dx.doi.org/10.1212/WNL.0000000000003992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447400PMC
May 2017

Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy.

Am J Hum Genet 2016 Apr 31;98(4):597-614. Epub 2016 Mar 31.

Dr. John T. Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Electronic address:

Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3' UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants.
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http://dx.doi.org/10.1016/j.ajhg.2016.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833435PMC
April 2016

Characterization of the mitofusin 2 R94W mutation in a knock-in mouse model.

J Peripher Nerv Syst 2014 Jun;19(2):152-64

Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Charcot-Marie-Tooth disease (CMT) comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. As mutations in several genes cause axonal degeneration in CMT type 2, mutations in mitofusin 2 (MFN2) account for approximately 90% of the most severe cases, making it the most common cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility; yet the mechanism by which dominant mutations in this protein lead to neurodegeneration is still not fully understood. Furthermore, future pre-clinical drug trials will be in need of validated rodent models. We have generated a Mfn2 knock-in mouse model expressing Mfn2(R94W), which was originally identified in CMT patients. We have performed behavioral, morphological, and biochemical studies to investigate the consequences of this mutation. Homozygous inheritance leads to premature death at P1, as well as mitochondrial dysfunction, including increased mitochondrial fragmentation in mouse embryonic fibroblasts and decreased ATP levels in newborn brains. Mfn2(R94W) heterozygous mice show histopathology and age-dependent open-field test abnormalities, which support a mild peripheral neuropathy. Although behavior does not mimic the severity of the human disease phenotype, this mouse can provide useful tissues for studying molecular pathways associated with MFN2 point mutations.
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http://dx.doi.org/10.1111/jns5.12066DOI Listing
June 2014

Motor protein mutations cause a new form of hereditary spastic paraplegia.

Neurology 2014 Jun 7;82(22):2007-16. Epub 2014 May 7.

From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.

Objective: To identify a novel disease gene in 2 families with autosomal recessive hereditary spastic paraplegia (HSP).

Methods: We used whole-exome sequencing to identify the underlying genetic disease cause in 2 families with apparently autosomal recessive spastic paraplegia. Endogenous expression as well as subcellular localization of wild-type and mutant protein were studied to support the pathogenicity of the identified mutations.

Results: In 2 families, we identified compound heterozygous or homozygous mutations in the kinesin gene KIF1C to cause hereditary spastic paraplegia type 58 (SPG58). SPG58 can be complicated by cervical dystonia and cerebellar ataxia. The same mutations in a heterozygous state result in a mild or subclinical phenotype. KIF1C mutations in SPG58 affect the domains involved in adenosine triphosphate hydrolysis and microtubule binding, key functions for this microtubule-based motor protein.

Conclusions: KIF1C is the third kinesin gene involved in the pathogenesis of HSPs and is characterized by a mild dominant and a more severe recessive disease phenotype. The identification of KIF1C as an HSP disease gene further supports the key role of intracellular trafficking processes in the pathogenesis of hereditary axonopathies.
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http://dx.doi.org/10.1212/WNL.0000000000000479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105256PMC
June 2014

The role of PGC-1 coactivators in aging skeletal muscle and heart.

IUBMB Life 2012 Mar 25;64(3):231-41. Epub 2012 Jan 25.

Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, FL, USA.

Aging is the progressive decline in cellular, tissue, and organ function. This complex process often manifests as loss of muscular strength, cardiovascular function, and cognitive ability. Mitochondrial dysfunction and decreased mitochondrial biogenesis are believed to participate in metabolic abnormalities and loss of organ function, which will eventually contribute to aging and decreased lifespan. In this review, we discuss what is currently known about mitochondrial dysfunction in the aging skeletal muscle and heart. We focused our discussion on the role of PGC-1 coactivators in the regulation of mitochondrial biogenesis and function and possible therapeutic benefits of increased mitochondrial biogenesis in compensating for mitochondrial dysfunction and circumventing aging and aging-related diseases.
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http://dx.doi.org/10.1002/iub.608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080206PMC
March 2012

Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.

J Clin Invest 2012 Feb 9;122(2):538-44. Epub 2012 Jan 9.

Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.

Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
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http://dx.doi.org/10.1172/JCI60560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266795PMC
February 2012

Mitochondrial DNA transcription regulation and nucleoid organization.

J Inherit Metab Dis 2011 Aug 4;34(4):941-51. Epub 2011 May 4.

Departments of Neurology, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.

Mitochondrial biogenesis is a complex process depending on both nuclear and mitochondrial DNA (mtDNA) transcription regulation to tightly coordinate mitochondrial levels and the cell's energy demand. The energy requirements for a cell to support its metabolic function can change in response to varying physiological conditions, such as, proliferation and differentiation. Therefore, mitochondrial transcription regulation is constantly being modulated in order to establish efficient mitochondrial oxidative metabolism and proper cellular function. The aim of this article is to review the function of major protein factors that are directly involved in the process of mtDNA transcription regulation, as well as, the importance of mitochondrial nucleoid structure and its influence on mtDNA segregation and transcription regulation. Here, we discuss the current knowledge on the molecular mode of action of transcription factors comprising the mitochondrial transcriptional machinery, as well as the action of nuclear receptors on regulatory regions of the mtDNA.
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http://dx.doi.org/10.1007/s10545-011-9330-8DOI Listing
August 2011

In vivo methylation of mtDNA reveals the dynamics of protein-mtDNA interactions.

Nucleic Acids Res 2009 Nov 9;37(20):6701-15. Epub 2009 Sep 9.

Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33136, USA.

To characterize the organization of mtDNA-protein complexes (known as nucleoids) in vivo, we have probed the mtDNA surface exposure using site-specific DNA methyltransferases targeted to the mitochondria. We have observed that DNA methyltransferases have different accessibility to different sites on the mtDNA based on the levels of protein occupancy. We focused our studies on selected regions of mtDNA that are believed to be major regulatory regions involved in transcription and replication. The transcription termination region (TERM) within the tRNA(Leu(UUR)) gene was consistently and strongly protected from methylation, suggesting frequent and high affinity binding of mitochondrial transcription termination factor 1 (mTERF1) to the site. Protection from methylation was also observed in other regions of the mtDNA, including the light and heavy strand promoters (LSP, HSP) and the origin of replication of the light strand (OL). Manipulations aiming at increasing or decreasing the levels of the mitochondrial transcription factor A (TFAM) led to decreased in vivo methylation, whereas manipulations that stimulated mtDNA replication led to increased methylation. We also analyzed the effect of ATAD3 and oxidative stress in mtDNA exposure. Our data provide a map of human mtDNA accessibility and demonstrate that nucleoids are dynamically associated with proteins.
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http://dx.doi.org/10.1093/nar/gkp727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777446PMC
November 2009