A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type 1b

Corrado, Lucia; Magri, Stefania; Bagarotti, Alessandra; Carecchio, Miryam; Piscosquito, Giuseppe; Pareyson, Davide; Varrasi, Claudia; Vecchio, Domizia; Zonta, Andrea; Cantello, Roberto; Taroni, Franco; D’Alfonso, Sandra

doi:10.1016/j.nmd.2016.05.011

Cited by 21 publications

(23 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar findings have been reported in other disorders, (26)(27)(28)(29)(30)(31)(32) also including skeletal defects (33)(34)(35) ; nonetheless, the contribution of synonymous mutations to human pathologies is likely highly underestimated at present. Although performing functional evaluations of all the synonymous changes in an individual exome is not cost-effective, it might be worth assessing the effect of those located in genes already known to be associated with diseases.…”

Section: Discussionsupporting

confidence: 84%

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Palagano

Susani

Menale

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Autosomal recessive osteopetroses (AROs) are rare, genetically heterogeneous skeletal diseases with increased bone density that are often lethal if left untreated. A precise molecular classification is relevant for the patient's management, because in some subgroups hematopoietic stem cell transplantation (HSCT), which is the only curative therapy, is contraindicated. In two unrelated ARO patients, the molecular analysis revealed the presence of a synonymous variant in known ARO genes, namely in the TCIRG1 gene in one patient and in the CLCN7 in the other patient, predicted to impact on the splicing process. In the latter case, sequencing of the transcript confirmed the splicing defect, whereas in the former, for whom an RNA sample was not available, the defect was reconstructed in vitro by the minigene technology. These results strongly suggest that these synonymous changes were responsible for the disease in our patients. Our findings are novel with respect to ARO and add to the few reports in literature dealing with different diseases, underlining the importance of cDNA analysis for the correct assessment of exonic changes, even when exome sequencing is performed. In particular, we highlight the possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, and suggest carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis. In addition, with respect to the CLCN7 gene, we suggest that synonymous variants might also contribute to the large spectrum of severity typical of CLCN7-dependent osteopetrosis through more subtle, but not negligible, effects on protein availability and functionality. © 2016 American Society for Bone and Mineral Research.

show abstract

Section: Discussionsupporting

confidence: 84%

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Palagano

Susani

Menale

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Because of the large number of genes implicated in this heterogeneous group of disease, this and other studies [22,23,24,25] together highlight the practical advantage of high-throughput sequencing in rapidly reaching the specific genetic diagnosis over previously proposed stepwise diagnostic algorithms [26,27,28]. As illustrated in Case 1, the patient had undergone screening for PMP22 duplication, mutation of GJB1 and MFN2 and active investigation for more than two years before the gene-panel method was attempted.…”

Section: Discussionmentioning

confidence: 93%

Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

Tai

Lee

et al. 2017

IJMS

View full text Add to dashboard Cite

Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygous HSPB1:NM_001540:c.250G>A (p.G84R) variant and heterozygous GDAP1:NM_018972:c.358C>T (p.R120W) variant, respectively. Advantages and limitations of the current approach are discussed.

show abstract

“…The proband and her daughter were found negative for mutations in the genes most frequently associated with axonal CMT (ie, MPZ , GJB1 , MFN2 , GDAP1 ). The proband then underwent a targeted resequencing analysis using an NGS customized probe‐based gene panel which included 117 disease genes causative for demyelinating and axonal Charcot‐Marie‐Tooth disease and other related peripheral neuropathies. Data analysis revealed the presence of the heterozygous pathogenic missense mutation NM_000399.3:c.1235A>G (p.E412G) in the EGR2 gene which was confirmed by Sanger sequencing and segregated with the disease in the family.…”

Section: Resultsmentioning

confidence: 99%

A novel family with axonal Charcot‐Marie‐Tooth disease caused by a mutation in the EGR2 gene

Tozza

Magri

Pennisi

et al. 2019

J Peripheral Nervous Sys

View full text Add to dashboard Cite

EGR2 (Early Growth Response 2) is one of the most important transcription factors involved in myelination in the peripheral nervous system. EGR2 mutations typically cause different forms of demyelinating neuropathy, that is, Charcot‐Marie‐Tooth type 1D (CMT1D), Dejerine‐Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN). However, the EGR2 gene has been recently associated with an axonal phenotype (CMT2) in a large CMT family. Here, we report another CMT family exhibiting an axonal phenotype associated with a missense change (c.1235A>G, p.E412G) in the EGR2 gene. Neurological evaluation of five affected members of the family showed a classical CMT phenotype including distal muscle atrophy and weakness, absence of deep tendon reflexes, pes cavus, and scoliosis. Electrophysiological examination was consistent with a motor‐sensory axonal neuropathy. Sural nerve biopsy performed in one patient showed a loss of myelinated and unmyelinated nerve fibers without de‐remyelinating signs and onion bulbs. This study confirms the phenotypical heterogeneity of EGR2‐related neuropathy, indicating a role for EGR2 in primary axonal degeneration.

show abstract

A novel synonymous mutation in the MPZ gene causing an aberrant splicing pattern and Charcot-Marie-Tooth disease type 1b

Cited by 21 publications

References 9 publications

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

A novel family with axonal Charcot‐Marie‐Tooth disease caused by a mutation in the EGR2 gene

Contact Info

Product

Resources

About