<i>ATP1A1</i>mutations cause intermediate Charcot‐Marie‐Tooth disease

He, J.; Guo, Lingling; Lin, Shujing; Chen, Wenfeng; Xu, Guiyin; Cai, Bin; Xu, Litao; Hong, Jing-Mei; Qiu, Liangliang; Wang, Ning; Chen, Wan‐Jin

doi:10.1002/humu.23886

Cited by 12 publications

(17 citation statements)

References 47 publications

(61 reference statements)

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“…Subsequently, heterozygous de novo mutations in ATP1A1 were reported in individuals with renal hypomagnesemia, refractory seizures, and intellectual disability, 28 and in a child with spastic paraplegia and intellectual disability with normal nerve conduction 29 . Our patient with the new AD variant in the ATP1A1 gene (p.Gly549Arg) had no pyramidal signs or intellectual disability at examination, and his CMT could be classified as intermediate, in accordance with previous observations from two Chinese families 30 . The child carrying the p.Arg381His variant in the EGR2 gene suffered from a very severe demyelinating phenotype but did not show signs of cranial neuropathy.…”

Section: Discussionsupporting

confidence: 89%

“…29 Our patient with the new AD variant in the ATP1A1 gene (p.Gly549Arg) had no pyramidal signs or intellectual disability at examination, and his CMT could be classified as intermediate, in accordance with previous observations from two Chinese families. 30 The child carrying the p.Arg381His variant in the EGR2 gene suffered from a very severe demyelinating phenotype but did not show signs of cranial neuropathy. This same EGR2 mutation was previously associated with severe demyelinating CMT with cranial nerve involvement.…”

Section: Discussionmentioning

confidence: 99%

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Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center

Argente‐Escrig

Frasquet

Vázquez-Costa

et al. 2021

Ann Clin Transl Neurol

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Background Single‐center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs). Methods Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well‐defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot–Marie–Tooth disease Pediatric Scale (CMTPedS). Results From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (±3.7) over 1 year (p < 0.0005, n = 62) and a 2‐year rate of 3.6 (±4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 ± 3.6, p < 0.05) and 2 years (4.2 ± 4.3, p < 0.0005). Conclusions This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center

Argente‐Escrig

Frasquet

Vázquez-Costa

et al. 2021

Ann Clin Transl Neurol

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“…To further rule out that mutations in iCERES cause misfolding triggering ER quality control, we performed cycloheximide-based pulse-chase experiments. The clearance of misfolded proteins from the ER by ERAD is fast and efficient [37,38], and pulse chase experiments of a wide variety of different transmembrane proteins, where mutations result in misfolding, revealed that already after one to two hours most of the unfolded protein is degraded [38][39][40][41][42]. As a control we used again the miR2_L438P mutation, which was deliberately designed to get misfolding and already showed more calnexin binding.…”

Section: Mutating Iceres Results In An Increased Half-life Of Irhom2 mentioning

confidence: 99%

The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release

Düsterhöft

Kahveci-Türköz

Wozniak

et al. 2021

Cell. Mol. Life Sci.

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Membrane-tethered signalling proteins such as TNFα and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the transport, maturation and activity of ADAM17. Yet, the structural and functional requirements to promote the transport of the iRhom-ADAM17 complex have not yet been thoroughly investigated. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and provide first insights into its structure and function. By focusing on iRhom2, we identified different structural and functional factors within the IRHD. We found that the structural integrity of the IRHD is a key factor for ADAM17 binding. In addition, we identified a highly conserved motif within an unstructured region of the IRHD, that, when mutated, restricts the transport of the iRhom-ADAM17 complex through the secretory pathway in in vitro, ex vivo and in vivo systems and also increases the half-life of iRhom2 and ADAM17. Furthermore, the disruption of this IRHD motif was also reflected by changes in the yet undescribed interaction profile of iRhom2 with proteins involved in intracellular vesicle transport. Overall, we provide the first insights into the forward trafficking of iRhoms which is critical for TNFα and EGF receptor signalling.

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“…In contrast to patients with de novo variants, patients with inherited variants are mainly presented CMT. Eight patients had familiar ATP1A1 mutation-related autosomal dominant CMT, one of them inherited the mutation from his mother with mosaic mutation (3,8). The inheritance mode of one case with CMT could not be confirmed due to lacking of the father's genetic test (3).…”

Section: Discussionmentioning

confidence: 98%

“…ATP1A1 variants may cause Na + /K + -ATPase loss of function and abnormal cation permeability, leading to membrane depolarization and impairment of the activity of the physiological pump and thus to diseases (5). Previous studies have reported a range of diseases related to ATP1A1 mutations, including renal hypomagnesemia, refractory epilepsy, intellectual disability, Charcot-Marie-Tooth disease (CMT), HSP, and aldosterone adenoma (3,(6)(7)(8)(9)(10)(11)(12). However, the phenotypes related to ATP1A1 de novo mutations were different from those with inherited mutations and have not been well-analyzed.…”

Section: Introductionmentioning

confidence: 99%

ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features

Lin

et al. 2021

Front. Pediatr.

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Background:ATP1A1 encodes an α1 isoform of Na+/K+-ATPase, which is expressed abundantly in kidneys and central nervous system. ATP1A1 variants may cause Na+/K+-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of ATP1A1 de novo mutation-related disorders and explore the potential correlations between phenotypes and genotypes.Methods: We analyzed two new cases harboring novel de novo ATP1A1 variants and reviewed all reported cases.Results: Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability, and patient 2 with refractory seizures. They each had a novel de novo heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with de novo ATP1A1 variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP). Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures.Conclusions: Two novel de novo ATP1A1 variants identified in two patients here enriched the genotypic and phenotypic spectrum of ATP1A1 mutation-related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na+/K+-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe ATP1A1 functional defect.

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ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

Cited by 12 publications

References 47 publications

Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center

Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center

The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release

ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features

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