L1CAM – MASA syndrome

L1CAM encodes the L1 cell adhesion molecule, a transmembrane glycoprotein essential for neuronal migration, axon guidance and fasciculation. MASA syndrome (MONDO:0010559) manifests as intellectual disability, aphasia, shuffling gait and adducted thumbs in hemizygous males, reflecting X-linked recessive inheritance with carrier females typically unaffected.

Genetic evidence for a definitive association includes multiple independent case reports of truncating and missense variants segregating with MASA or overlapping phenotypes. A five-nucleotide deletion in exon 8 causing a frameshift and premature stop codon was found in two affected brothers and a heterozygous sister ([PMID:8786080]). A single-base deletion in exon 22 yielding a truncated protein lacking the transmembrane domain was identified in a 9-year-old boy with hydrocephalus and MASA features, segregating with carrier females ([PMID:9440802]). The first MASA‐only case in Asia harbored a novel nonsense variant c.3496C>T (p.Arg1166Ter) in exon 26 ([PMID:15904436]).

In a cohort of eight unrelated MASA patients, three distinct L1CAM variants—including the recurrent missense c.1792G>A (p.Asp598Asn)—were described, confirming allelic heterogeneity ([PMID:7920660]). Broader surveys identified >34 unique L1CAM mutations across MASA and related HSAS/SPG1 spectra in over 30 families ([PMID:8826452]). These data establish a robust genotype–phenotype correlation with X-linked recessive transmission.

Functional assays demonstrate loss-of-function as the primary mechanism. Most missense mutations in the extracellular domain reduce homophilic and heterophilic ligand binding and impede cell surface trafficking in COS/CHO cells ([PMID:11772994]). Variants such as p.Arg184Gln and p.Trp1036Leu induce partial ER retention with decreased neurite outgrowth in neuronal models ([PMID:20621658]).

No conflicting studies dispute the L1CAM–MASA link. Data from diverse populations and functional concordance across assays reinforce a definitive gene–disease relationship supported by both genetic and experimental evidence.

Key take-home: L1CAM loss-of-function variants cause MASA syndrome via disrupted neuronal adhesion, providing actionable targets for molecular diagnosis, genetic counselling and prenatal testing.

References

• Human genetics • 1996 • A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus. PMID:8786080
• Brain & development • 1997 • L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling. PMID:9440802
• Congenital anomalies • 2005 • First case of L1CAM gene mutation identified in MASA syndrome in Asia. PMID:15904436
• Nature genetics • 1994 • MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM. PMID:7920660
• American journal of medical genetics • 1996 • The clinical spectrum of mutations in L1, a neuronal cell adhesion molecule. PMID:8826452
• Human molecular genetics • 2002 • Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. PMID:11772994
• Neurobiology of disease • 2010 • L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms. PMID:20621658

Evidence Based Scoring (AI generated)