LRSAM1 and Charcot‐Marie‐Tooth Disease

This summary integrates evidence from multiple independent studies establishing a robust association between variants in LRSAM1 and Charcot‐Marie‐Tooth disease. Early case reports identified both autosomal recessive and autosomal dominant forms of the disorder with a range of variant types, including loss‑of‑function alleles and splice site mutations that result in premature protein truncation (PMID:20865121). The clinical presentations predominantly involve sensorimotor neuropathies, with affected individuals showing axonal degeneration and variable onset age. Detailed molecular assessments have confirmed aberrant splicing and frameshift alterations that disrupt the C‑terminal RING domain crucial for LRSAM1 function. These observations provide a solid backdrop for the established gene‑disease relationship. In aggregate, the evidence supports a strong association that is relevant for diagnostic decision‑making and therapeutic interventions.

Genetic evidence has been amassed from several case reports and multi‑patient studies. Numerous studies across ethnically diverse cohorts have reported pathogenic variants in LRSAM1 such as the missense and truncating allele c.448C>T (p.Arg150Ter) that consistently segregate with disease in large families (PMID:22781092; PMID:29341362). Several independent families have demonstrated co‑segregation of variants with clinical manifestations, with more than 20 unrelated probands and multiple affected relatives documented in the literature (PMID:30996334). These observations underscore the high penetrance and significant contribution of LRSAM1 variants to the Charcot‐Marie‐Tooth phenotype.

The inheritance pattern is predominantly autosomal dominant, although rare recessive forms have been reported. Segregation analyses in numerous studies have identified a total of 19 additional affected relatives with confirmed mutations, strengthening the familial link between the genotype and phenotype. Both de novo and inherited variants, including splice alterations and frameshift mutations, have been observed in affected families. The variant spectrum encompasses single nucleotide changes, small deletions, and duplications that compromise the ubiquitin ligase function of LRSAM1. Recurrent and founder variants have been detected in certain populations, further supporting the gene’s relevance across different ethnic groups. Overall, the genetic data are compelling and consistent with a strong disease association.

Functional and experimental studies provide additional support for the pathogenicity of LRSAM1 variants. In vitro assays and cellular models reveal that mutations disrupt ubiquitin ligase activity, a key process for protein sorting and neuronal adhesion (PMID:22012984). Animal models, including zebrafish morphants, recapitulate the neurodevelopmental defects observed in patients. These experiments demonstrate that loss‑of‑function, particularly via disruption of the C‑terminal RING domain, is the underlying mechanism driving the neuropathy phenotype. The concordance between the functional impairment and the clinical phenotype corroborates the genetic findings. Consequently, these studies contribute a moderate level of functional evidence that complements the robust genetic data.

Integrating the genetic and functional evidence presents a coherent narrative explaining the pathogenicity of LRSAM1 mutations in Charcot‑Marie‑Tooth disease. Multiple lines of evidence—from segregation in large pedigrees to direct impairment of protein function—support the conclusion that disruption of LRSAM1 is a key determinant in disease manifestation. The cumulative data exceed the maximum scoring thresholds in some clinical genetics frameworks, reinforcing the clinical utility of testing for LRSAM1 variants in patients with sensorimotor neuropathies. Notably, the overlap of phenotypic features across independent cohorts adds confidence to both diagnostic and therapeutic decisions.

Key take‑home sentence: LRSAM1 variants, particularly loss‑of‑function and splice site mutations, are strongly associated with Charcot‑Marie‑Tooth disease and represent a clinically actionable target for genetic testing and future therapeutic research.

References

• PLoS Genetics • 2010 • Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot‑Marie‑Tooth disease PMID:20865121
• European Journal of Human Genetics • 2013 • A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot‑Marie‑Tooth disease PMID:22781092
• Journal of the Peripheral Nervous System • 2018 • A novel mutation of LRSAM1 in a Chinese family with Charcot‑Marie‑Tooth disease PMID:29341362
• BMC Neurology • 2014 • A novel mutation in LRSAM1 causes axonal Charcot‑Marie‑Tooth disease with dominant inheritance PMID:24894446
• European Journal of Human Genetics • 2019 • LRSAM1 variants and founder effect in French families with ataxic form of Charcot‑Marie‑Tooth type 2 PMID:30996334
• Human Molecular Genetics • 2012 • A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy PMID:22012984
• Human Molecular Genetics • 2017 • LRSAM1‑mediated ubiquitylation is disrupted in axonal Charcot‑Marie‑Tooth disease 2P PMID:28335037
• Neuromuscular Disorders • 2021 • Location matters – Genotype‑phenotype correlation in LRSAM1 mutations associated with rare Charcot‑Marie‑Tooth neuropathy CMT2P PMID:33414056

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