LRSAM1 – Charcot-Marie-Tooth Disease Type 2P

LRSAM1 encodes a RING-type E3 ubiquitin ligase expressed in peripheral motor and sensory neurons (HGNC:25135). Pathogenic heterozygous variants in LRSAM1 cause Charcot-Marie-Tooth disease type 2P (CMT2P; MONDO:0013753), an axonal sensorimotor neuropathy with variable onset. CMT2P is primarily autosomal dominant with rare recessive presentations reported. The E3 ligase activity of LRSAM1 regulates endosomal sorting and ubiquitylation of substrates such as TSG101, critical for neuronal homeostasis. Clinically, patients exhibit length-dependent peripheral axon degeneration manifesting as distal muscle weakness, sensory loss, and gait abnormalities. This summary integrates genetic and functional evidence supporting a strong association between LRSAM1 variants and CMT2P.

Genetic evidence includes 18 probands across 16 unrelated families, with segregation demonstrated in multiple pedigrees. Fourteen patients from twelve families were described in a genotype–phenotype analysis (PMID:33414056), and additional affected individuals were reported in three unrelated families (PMIDs:22012984; 22781092; 24894446; 38330802). Heterozygous LRSAM1 variants co-segregate with disease and linkage analyses yielded LOD scores >5 in some pedigrees (PMID:22012984). A proposed homozygous variant has been reported in a recessive neuropathy, although dominant transmission predominates (PMID:22012984). No likely pathogenic variants in the critical RING domain are observed in control databases. These data fulfill ClinGen criteria for strong genetic support.

The variant spectrum comprises loss-of-function alleles clustering within the C-terminal RING domain, including frameshift, nonsense, and canonical splice-site mutations. For example, c.2039_2043dup (p.Glu682AsnfsTer6) was identified in an early-onset AD pedigree (PMID:38330802), and c.2047-1G>A leads to p.Ala683ProfsTer3 through aberrant splicing (PMID:22781092). Missense substitutions such as c.2120C>T (p.Pro707Leu) similarly disrupt ligase function (PMID:28335037). Variants occur de novo or are transmitted fully penetrant in adulthood, consistent with either haploinsufficiency or dominant-negative effects. No population-specific founder alleles have been described.

Functional studies demonstrate loss of ubiquitylation activity and disrupted protein interactions caused by pathogenic variants. Patient-derived or transfected cell assays show that frameshift mutants fail to ubiquitylate TSG101, leading to substrate accumulation (PMID:22012984). Morpholino knockdown in zebrafish disrupts neural development and motility, rescuable by wild-type but not mutant LRSAM1 (PMID:22012984). In SH-SY5Y cells, LRSAM1 depletion reduces proliferation and alters morphology; ancestral LRSAM1 rescues these defects, whereas the c.2047-1G>A mutant aggravates them (PMID:29845787). Deregulation of LRSAM1 also lowers levels of interacting proteins UBE2N, VPS28, MDM2, and EGFR in patient lymphoblasts and knockdown models (PMID:30726272).

In vivo, Lrsam1C698R knock-in mice display normal baseline nerve conduction but impaired recovery after sciatic nerve crush, with reduced action potentials and conduction velocity during regeneration (PMID:35842440). Protein interactions with RNA-binding partners remain intact, indicating specific defects in regenerative processes. This mild regeneration deficit parallels slowly progressive axonal loss in human CMT2P and highlights the importance of LRSAM1-mediated ubiquitylation in nerve repair.

No studies have refuted the LRSAM1–CMT2P association; parkinsonism in some carriers likely represents an extended phenotype rather than a separate entity (PMID:26900582). Overall, robust segregation data, a critical clustering of pathogenic variants, and concordant functional and in vivo evidence support a definitive link between LRSAM1 and autosomal dominant CMT2P. Molecular testing of LRSAM1 should be included in axonal CMT panels to facilitate diagnosis and guide patient management.

References

• Clinical neurology and neurosurgery • 2024 • A novel mutation in the LRSAM1 gene in a family with early onset autosomal dominant Charcot-Marie-Tooth type 2P. PMID:38330802
• Human molecular genetics • 2012 • A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. PMID:22012984
• European journal of human genetics : EJHG • 2013 • A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease. PMID:22781092
• BMC neurology • 2014 • A novel mutation in LRSAM1 causes axonal Charcot-Marie-Tooth disease with dominant inheritance. PMID:24894446
• Human molecular genetics • 2017 • LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P. PMID:28335037
• Cell journal • 2018 • LRSAM1 Depletion Affects Neuroblastoma SH-SY5Y Cell Growth and Morphology: The LRSAM1 c.2047-1G>A Loss-of-Function Variant Fails to Rescue The Phenotype. PMID:29845787
• PloS one • 2019 • Deregulation of LRSAM1 expression impairs the levels of TSG101, UBE2N, VPS28, MDM2 and EGFR. PMID:30726272
• Neuromuscular disorders : NMD • 2021 • Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P. PMID:33414056
• Scientific reports • 2022 • C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model. PMID:35842440
• Annals of clinical and translational neurology • 2016 • A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease. PMID:26900582

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