Location matters – Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P

Reilich, Peter; Schlotter, Beate; Montagnese, Federica; Jordan, Berit; Stock, Friedrich; Schäff-Vogelsang, Mario; Hotter, Benjamin; Eger, Katherina; Diebold, Isabel; Erdmann, Hannes; Becker, Kerstin; Schön, Ulrike; Schöser, Benedikt

doi:10.1016/j.nmd.2020.11.011

Cited by 4 publications

(5 citation statements)

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“…CMT2P is caused by autosomal dominant and recessive mutations in leucine rich repeat and sterile alpha motif 1 (LRSAM1) gene on human chromosome-9 [4][5][6][7][8][9][10][11][12] . Most patients with autosomal dominant CMT2P usually manifest a teenage or adult-onset, slowly progressive, length-dependent sensory-motor axonal polyneuropathy 5,6,11,13 .…”

Section: Introductionmentioning

confidence: 99%

C698R Lrsam1 knock-in mouse model for CMT2P

Moiseev

Wazir

Liu

et al. 2022

Preprint

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Objective: Missense mutation C694R in the RING domain of the LRSAM1 gene results in a dominantly inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2P (CMT2P). In this study, we have generated a Lrsam1C698R knock-in mouse model, which was extensively characterized. Methods: Mice with a heterozygous Lrsam1+/C698R mutation were generated by CRISPR/Cas9 technology. The C698R Lrsam1 knock-in mice were evaluated clinically using Rotarod and hindlimb clasping tests, physiologically by nerve conduction studies, morphologically on nerve sections. Results: Heterozygous (Lrsam1+/C698R) and homozygous knock-in (Lrsam1C698/C698R) mice exhibited normal motor functions on behavioral tests and nerve conduction studies. Axonal density and myelin thickness were not significantly different between mutants and wild-type mice by sciatic nerve morphometric analysis up to 17 months of age. In line with the normal findings in native mice, interactions between mutant LRSAM1 and RNA-binding proteins (such as FUS and G3BP1) were still present in mouse cells, which differs from the disrupted protein-protein interactions in human CMT2P cells. However, after crush nerve injury, Lrsam1+/C698R mice had a mild, but statistically significant, reduced compound nerve action potential (CMAP) and conduction velocity (CV) during recovery.Interpretation: C698R mutation results in mild impairment of nerve regeneration in mice. We speculate that repetitive nerve injuries may, at least partially, contribute to the slowly progressive axonal loss in CMT2P.

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Section: Introductionmentioning

confidence: 99%

C698R Lrsam1 knock-in mouse model for CMT2P

Moiseev

Wazir

Liu

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…CMT2P is caused by autosomal dominant and recessive mutations in leucine rich repeat and sterile alpha motif 1 ( LRSAM1 ) gene on human chromosome-9 4 – 12 . Most patients with autosomal dominant CMT2P usually manifest a teenage or adult-onset, slowly progressive, length-dependent sensory-motor axonal polyneuropathy 5 , 6 , 11 , 13 .…”

Section: Introductionmentioning

confidence: 99%

C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model

Moiseev

Wazir

Liu

et al. 2022

Sci Rep

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Missense mutation C694R in the RING domain of the LRSAM1 gene results in a dominantly inherited polyneuropathy, Charcot-Marie-Tooth disease type 2P (CMT2P). We have generated and characterized a Lrsam1C698R knock-in mouse model produced through CRISPR/Cas9 technology. Both heterozygous (Lrsam1+/C698R) and homozygous (Lrsam1C698/C698R) knock-in mice exhibited normal motor functions on behavioral tests as well as normal on nerve conduction studies. Axonal density and myelin thickness were not significantly different between mutants and wild-type mice by sciatic nerve morphometric analysis up to 17 months of age. In line with these normal findings, protein–protein interactions between mutant LRSAM1 and RNA-binding proteins (such as FUS and G3BP1) were still present in mouse cells, which differs from the disrupted interactions between these proteins in human CMT2P cells. However, after crush nerve injury, Lrsam1+/C698R mice had a mild, but statistically significant, reduced compound nerve action potential and conduction velocity during recovery. Therefore, C698R mutation results in a mild impaired nerve regeneration in mice. We speculate that repetitive nerve injuries may, at least partially, contribute to the slowly progressive axonal loss in CMT2P.

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“…As variantes encontradas neste trabalho (p.Glu312AlafsTer48 e p.Arg315Leu) não foram descritas na literatura e nós as classificamos como ___________________________________________________________________ 103 DISCUSSÃO provavelmente patogênica e VUS respectivamente (os critérios utilizados para classificação das variantes estão disponíveis no apêndice C, páginas 150 e 157 respectivamente). Existem vários estudos relatando variantes no gene LRSAM1 responsáveis pelo fenótipo de CMT2P que é, em geral, caracterizado por uma neuropatia axonal de início tardio (10-56 anos) com comprometimento predominantemente sensitivo, déficit motor lentamente progressivo, atrofia e deformidades nos pés (ENGEHOLM et al, 2014;GUERNSEY et al, 2010;PALAIMA et al, 2021;PERETTI et al, 2019;REILICH et al, 2021). Além disso, ataxia acentuada da marcha, dor neurogênica, envolvimento do sistema nervoso autônomo (como disfunção erétil e problemas urinários) e elevação da creatina quinase (CK) também já foram relatadas (ENGEHOLM et al, 2014;GUERNSEY et al, 2010;REILICH et al, 2021).…”

Section: Naglu Pnkp E Slc5a7)unclassified

“…Existem vários estudos relatando variantes no gene LRSAM1 responsáveis pelo fenótipo de CMT2P que é, em geral, caracterizado por uma neuropatia axonal de início tardio (10-56 anos) com comprometimento predominantemente sensitivo, déficit motor lentamente progressivo, atrofia e deformidades nos pés (ENGEHOLM et al, 2014;GUERNSEY et al, 2010;PALAIMA et al, 2021;PERETTI et al, 2019;REILICH et al, 2021). Além disso, ataxia acentuada da marcha, dor neurogênica, envolvimento do sistema nervoso autônomo (como disfunção erétil e problemas urinários) e elevação da creatina quinase (CK) também já foram relatadas (ENGEHOLM et al, 2014;GUERNSEY et al, 2010;REILICH et al, 2021). Alguns estudos também sugerem a possibilidade de uma associação clínica de CMT2P com doenças neurodegenerativas do sistema nervoso central pela presença de Parkinson em alguns pacientes (AERTS et al, 2016;PERETTI et al, 2019).…”

Section: Naglu Pnkp E Slc5a7)unclassified

“…Alguns estudos também sugerem a possibilidade de uma associação clínica de CMT2P com doenças neurodegenerativas do sistema nervoso central pela presença de Parkinson em alguns pacientes (AERTS et al, 2016;PERETTI et al, 2019). Variantes recessivas nesse gene são raras e foi descrita em apenas duas famílias, uma do Canadá e outra da Austrália (GUERNSEY et al, 2010;REILICH et al, 2021). A maioria das variantes patogênicas descritas nesse gene estão localizados no domínio RING (C-terminal; aminoácidos 675-710) mostrando a importância desse domínio para a correta função da proteína (PALAIMA et al, 2021).…”

Section: Naglu Pnkp E Slc5a7)unclassified

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Caracterização genotípica de pacientes brasileiros pediátricos com a doença de Charcot-Marie-Tooth axonal utilizando tecnologias de sequenciamento de nova geração

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Location matters – Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P

Cited by 4 publications

References 33 publications

C698R Lrsam1 knock-in mouse model for CMT2P

C698R Lrsam1 knock-in mouse model for CMT2P

C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model

Caracterização genotípica de pacientes brasileiros pediátricos com a doença de Charcot-Marie-Tooth axonal utilizando tecnologias de sequenciamento de nova geração

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