LRSAM1

Inheritance Pattern: AD

Disease ID:MONDO:0013753

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013753

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013753

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013753

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013753

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013753

Submitter: ClinGen

LRSAM1 was first reported in relation to autosomal dominant Charcot-Marie-Tooth disease axonal type 2P in 2012 in a large 3-generation Dutch family (Weterman et al., PMID: 22012984). Linkage analysis identified a region on chr9q33-34, further sequencing of candidate genes identified a frameshift variant in LRSAM1 gene segregating in all affected members. Patients presented during adulthood with slowly progressive axonal neuropathy and distal muscle weakness and atrophy. The disease was relatively mild with variable clinical severity and reduced penetrance. Although rare, there are 2 reports of autosomal recessive inheritance to date. The first dated back to 2010, where homozygosity mapping in a large Canadian family identified a single region on chr 9 and further sequencing revealed a homozygous splice variant c.1913-1G>A in all affected individuals (PMID: 20865121). More recently, one patient was reported homozygous for c.1913_1914del (PMID:33414056). Interestingly, both variants are predicted to have the same effect on the protein (p.Glu638AlafsX7) and loss of function was suggested to be the mechanism of pathogenicity. Patients reported to have a similar clinical presentation and age at onset compared to the AD CMT2P. Of note, the recessive inheritance was not included in this current curation and is just mentioned here until enough further evidence is available in the published literature. Leucine-rich repeat and sterile alpha motif containing 1 protein (LRSAM1) is involved in a number of cellular processes. With its E3 ubiquitin ligase activity, it modulates the protein aggregation and endosomal sorting machinery. LRSAM1 is highly expressed in human fetal and adult nervous system, primarily in motor neurons and spinal cord. In situ hybridization in murine embryonic sections showed a high level of expression in peripheral motor and sensory neurons. The LRSAM1 gene contains 26 exons, with all reported AD variants located in the penultimate or last exon, clustered in the hot spot RING domain. More than 60 variants including missense, frameshift, splice-site, nonsense, large deletions and duplications are reported in HGMD, with more than 150 patients with CMT2P reported in the literature (PMID: 33414056). Some of these reports were included in this curation (PMIDs: 22012984, 22781092, 27615052, 27686364, 30996334, 24894446). Expression of the mutant c.2080 T>C; p.(C694R) in Lrsam1 KO neuronal cell line resulted in axonal degeneration. Furthermore, the Cys694Arg variant altered interactions between LRSAM1 and RNA binding proteins (PMID: 27615052). Another functional study showed that depletion of LRASM1 in a neuronal cell model affected cell growth and morphology. This phenotype was rescued by overexpression of WT LRSAM1 but not with the c.2047-1G>A mutant (PMID: 29845787). This gene-disease relationship is also supported by a zebrafish model, where two different morpholino oligos were used to mimic the KO phenotype as well as the effect of the c.2121_2122dup variant. Both resulted in abnormal motor neuron development (PMID: 22012984). Furthermore, an Lrsam1 C698R knock-in mouse model was generated, where the equivalent of the human variant C694R was introduced into the mouse genome (PMID: 35842440). This model did not fully recapitulate the phenotype seen in patients as only mildly impaired nerve function during regeneration after nerve injury was observed. A knockout mouse model was also generated, mice presented with mild peripheral neuropathy and increased sensitivity to neurotoxic agent (PMID: 23519028). This model however might not be relevant to the AD disorder as the mechanism of disease is suggested to be dominant negative although further studies are needed (PMID:33414056, 28335037). In summary, there is definitive evidence supporting the relationship between LRSAM1 and autosomal dominant Charcot-Marie-Tooth disease axonal type 2P. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.