Clinical and biophysical characterization of 19 GJB1 mutations

Abstract

ObjectiveCharcot–Marie–Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta‐1 gene (GJB1), is the second most common form of Charcot–Marie–Tooth disease (CMT). GJB1 encodes the GJ beta‐1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.MethodsAll patients with a validated GJB1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+ permeability.ResultNineteen GJB1 mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions. GJB1 mutations that caused a complete loss of GJ Ca2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.InterpretationThis study demonstrated that the degree of loss of GJ function caused by the GJB1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.

Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury

“…8B) was built using the hub genes Car2, F2ah, Mbp and Plp1 that are all coding for major components of myelin [3,10] and together with cholesterol, are particularly important for myelin formation and remodeling in the context of axonal loss and repair after TBI [61,62]. Mutations in the majority of the genes within the network lead to demyelination and hypomyelinating inherited disorders [13,62,64,66], or have been implicated in neurodegeneration, including Alzheimer’s Disease. Alternatively, the high presence of myelin related proteins, including Mag , myelin associated glycoprotein, could be indicative of the formation of a glial scar [74,59].…”

Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

“…For most of the patients without PMP22 duplication and GJB1 mutations, further mutational analysis was performed by utilizing a high‐throughput targeted NGS panel for detecting mutations in other CMT‐related genes. For a minor group of the patients recruited before 2014, the mutation analyses were conducted by direct nucleotide sequencing of PMP22 (RefSeq NM_000304.3), MPZ (RefSeq NM_000530.5) , MFN2 (RefSeq NM_014874.3) , NEFL (RefSeq NM_006158.4), AARS (RefSeq NM_001605.2) , HSPB1 (RefSeq NM_001540.5), and GDAP1 (RefSrq NM_018972.3) as employed in our previous studies …”

X-linked Charcot-Marie-Tooth disease case with a novel missense mutation in GJB1 gene

“…Complete loss of gap junction Ca 2+ permeability and cytosolic expression of GJB1 appeared to be associated with an earlier disease onset and more severe phenotype (mean age of onset, 19 years old; mean CMTNS, 13.4), whereas preservation of gap junction permeability and predominant cell membrane expression of GJB1 tended to have a later onset and milder phenotype (mean age of onset, 35.8; mean CMTNS, 8.8) [3]. Moreover, phenotypes owing to nonsense or frameshift mutations appear to be more severe than those of missense mutations [3,7].…”

“…In terms of the genotype-phenotype correlation concerning basic functional studies, reduced GJB1 expression and intracellular localization leading to altered gap junction function in cell model has been suggested to have a positive correlation with more severe phenotypes [3]. Complete loss of gap junction Ca 2+ permeability and cytosolic expression of GJB1 appeared to be associated with an earlier disease onset and more severe phenotype (mean age of onset, 19 years old; mean CMTNS, 13.4), whereas preservation of gap junction permeability and predominant cell membrane expression of GJB1 tended to have a later onset and milder phenotype (mean age of onset, 35.8; mean CMTNS, 8.8) [3]. Moreover, phenotypes owing to nonsense or frameshift mutations appear to be more severe than those of missense mutations [3,7].…”

“…CMTX1 share common features with CMT such as progressive motor weakness, wasting of the lower extremities and foot deformities, hypoactive deep tendon reflexes (DTRs), and sensory abnormalities. Interestingly, CMTX1 has distinct features not found in most other types of CMT: the antecedent central nervous system (CNS) involvement, which involves white matter changes in magnetic resonance imaging (MRI) and magnetic resonance spectroscopy abnormalities [1][2][3]. CMTX1 follows X-linked dominant inheritance, and male patients are more severely affected than female patients.…”