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Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1

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Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1 brain sciences Article Aberrant Splicing in GJB1 and the Relevance of 50 UTR in CMTX1 Pathogenesis Federica Boso 1,2,† , Federica Taioli 1,†, Ilaria Cabrini 1, Tiziana Cavallaro 3 and Gian Maria Fabrizi 1,3,* 1 Department of Neurological Sciences, Biomedicine and Movement Sciences, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy; [email protected] (F.B.); [email protected] (F.T.); [email protected] (I.C.) 2 Department of Cellular, Computational and Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy 3 Azienda Ospedaliera Universitaria Integrata Verona—Borgo Roma, Piazzale L.A. Scuro 10, 37134 Verona, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0458124286 † These Authors contributed equally to the work. Abstract: The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 50 untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 50 UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels. Citation: Boso, F.; Taioli, F.; Cabrini, I.; Cavallaro, T.; Fabrizi, G.M. Aberrant Keywords: Charcot-Marie-Tooth; CMT; X-linked Charcot-Marie-Tooth (CMTX1); Connexin 32; GJB1; 0 Splicing in GJB1 and the Relevance of 5 UTR; noncoding; splicing 50 UTR in CMTX1 Pathogenesis. Brain Sci. 2021, 11, 24. https://dx. doi.org/10.3390/brainsci11010024 1. Introduction Received: 30 November 2020 Charcot-Marie-Tooth disease (CMT) refers to the most frequent group of hereditary Accepted: 23 December 2020 neuropathies, encompassing a wide range of genetic, clinical, neurophysiological and Published: 27 December 2020 pathological features. Despite significant genetic heterogeneity, most known mutations Publisher’s Note: MDPI stays neu- involve four genes (PMP22, GJB1, MFN2 and MPZ)[1,2], but, until recently, molecular tral with regard to jurisdictional claims diagnosis was hampered by a costly and gruelling search for those main causative genes in published maps and institutional by multiplex ligation-dependent probe amplification (MLPA) and conventional Sanger affiliations. sequencing using a candidate-gene approach. Indeed, the advent of next-generation se- quencing (NGS) techniques paved the way for a broader screening of the patients and for the discovery of rarer variants, thus providing a higher likelihood of identification. Notwithstanding this considerable progress, assuming a Mendelian inheritance, a genetic Copyright: © 2020 by the authors. Li- diagnosis remains elusive in 30–70% of CMT patients [1–4], depending on customized censee MDPI, Basel, Switzerland. This gene panels that generally cover only known disease-related coding sequences in order to article is an open access article distributed provide a faster and affordable analysis with higher coverage, as well as fewer incidental under the terms and conditions of the findings. As an example, the most frequent culprit for CMT after peripheral myelin protein Creative Commons Attribution (CC BY) 22 (PMP22) is the gap junction beta 1 protein gene (GJB1), affecting about 6.5–17% of the license (https://creativecommons.org/ patients with a presumptive inherited neuropathy [2,3]. Human GJB1 consists of two exons, licenses/by/4.0/). Brain Sci. 2021, 11, 24. https://dx.doi.org/10.3390/brainsci11010024 https://www.mdpi.com/journal/brainsci Brain Sci. 2021, 11, x FOR PEER REVIEW 2 of 11 Brain Sci. 2021, 11, 24 2 of 11 patients with a presumptive inherited neuropathy [2,3]. Human GJB1 consists of two ex- ons, separated by an intron of variable size: exon 1 encodes most of the 5′ untranslated region (UTR), whereas exon 2 encompasses the entire amino acid coding region and the separated by an intron of variable size: exon 1 encodes most of the 50 untranslated region 3′ UTR. Two different(UTR), whereas tissue-specific exon 2 promoters encompasses have the been entire acknowledged amino acid coding[5]: a basal region pro- and the 30 UTR. moter P1 is locatedTwo different more than tissue-specific 8 kb upstream promoters from the have coding been sequence acknowledged and regulates [5]: a basal the promoter P1 transcript NM_001097642is located more in liver, than 8pancreas, kb upstream oocytes from and the embryonic coding sequence stem cells, and regulateswhile in the transcript the peripheralNM_001097642 nervous system in, the liver, alternative pancreas, promoter oocytes andP2 (the embryonic 130-bp exon stem 1B, cells, which while is in the periph- separated fromeral exon nervous 2 by the system, 356-bp the intron alternative 1B) is promoter responsible P2 (thefor the 130-bp production exon 1B, of which the is separated transcript NM_000166.from exon By 2 alternative by the 356-bp promoter intron usage, 1B) is responsibleGJB1 thus provides for the production mRNAs with of the transcript identical codingNM_000166. regions but By different alternative 5′ UTR promoter with specific usage, cisGJB1-regulatorythus provides elements mRNAs (Sup- with identical plementary Figurecoding S1). regions Thanks but to differentthe broader 50 UTR availability with specific of genetic cis-regulatory screening, elementstoday there (Supplementary are over 450 knownFigure variants S1). Thanks in the to thecoding broader sequence, availability with ofa geneticmajority screening, of missense today muta- there are over 450 tions and rarerknown cases with variants frameshift in the codingand premature sequence, stop with codon a majority mutations of missense or ample mutations dele- and rarer tions. However,cases noncoding with frameshift regions are and increasingly prematurestop recognized codonmutations not only as or key ample regulators deletions. However, of protein expressions,noncoding but regions also as are potential increasingly hidden recognized causes of not diseases, only as keyaccounting regulators for ofso protein expres- much as 10% ofsions, patients but alsowith as GJB1 potential mutations hidden [3]. causes Indeed, of variations diseases, accountingof the UTR forma soy be- much as 10% of come pathogenicpatients by disrupting with GJB1 themutations sequences [3]. that Indeed, regulate variations transcription of the UTR (such may as becomebinding pathogenic by sites for transcriptiondisrupting factors the sequences like Early that Growth regulate Response transcription-2, EGR2 (such asand binding SRY-Box sites 10, for transcription SOX10) or by impairingfactors like mRNA Early translation Growth Response-2, and stability, EGR2 thus and influencing SRY-Box protein 10, SOX10) expres- or by impairing sion [6,7]. mRNA translation and stability, thus influencing protein expression [6,7]. We propose theWe candidate propose the variant candidate c.-17+1G>T variant c.-17+1G>Tas an example as an of examplea 5′ UTR of mutation a 50 UTR mutation that that may accountmay for account mRNA for instability mRNA instabilityby aberrant by splicing aberrant of splicingintron 1B, of ultimately intron 1B, caus- ultimately causing ing CMTX1. CMTX1. 2. Patients, Materials2. Patients, and MaterialsMethods and Methods Two young probandsTwo young who probands were evaluated who were for evaluateda length-dependent, for a length-dependent, sensory-motor sensory-motor neuropathy ledneuropathy to the study led of two to the unrelated study of families two unrelated on the assumption families on of thea genetic assumption path- of a genetic ogenesis (Figurepathogenesis 1A, II-2; Figure (Figure 1B,1A, III II-2;-9). FigureBoth cases1B, III-9). presented Both caseswith typical presented features with typicalof features CMT, reportingof walking CMT, reporting difficulties, walking sensory difficulties, abnormalities sensory and abnormalities slowly progressive and slowly distal progressive distal muscle weaknessmuscle with weakness peroneal withatrophy peroneal and foot atrophy deformities and foot. T deformities.he male proband The malealso had proband also had further clues suchfurther as cluesearly suchonset as(in early the second onset (in decade), the second split decade),hand syndrome, split hand postural syndrome, postural tremor and bilateraltremor hypoacusia. and bilateral Likewise, hypoacusia. pedigree Likewise, analysis pedigree revealed analysis similarly revealed affected similarly affected relatives (Tablerelatives 1), with (Table a tendency1), with for a males tendency to be for m malesore severely to be more and prematurely severely and affected prematurely affected and with no cases of male-to-male transmission, thus suggesting an X-linked dominant and with no cases of male-to-male transmission, thus suggesting
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