CRASH syndrome: mutations in L1CAM correlate with severity of the disease - PubMed (original) (raw)
CRASH syndrome: mutations in L1CAM correlate with severity of the disease
M Yamasaki et al. Neuropediatrics. 1997 Jun.
Abstract
X-linked hydrocephalus, MASA syndrome and certain forms of X-linked spastic paraplegia and agenesis of corpus callosum are now known to be due to mutations in the gene for the neural cell adhesion molecule L1 (19, 30). As a result, these syndromes have recently been reclassified as CRASH syndrome, an acronym for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spasticity and Hydrocephalus (8). A comparison of existing case reports with molecular genetic analysis reveals a striking correlation between the type of mutation in the L1CAM gene and the severity of the disease. Mutations that produce truncations in the extracellular domain of the L1 protein are more likely to produce severe hydrocephalus, grave mental retardation or early death than point mutations in the extracellular domain or mutations affecting only the cytoplasmic domain of the protein. While less severe than extracellular truncations, point mutations in the extracellular domain do produce more severe neurologic problems than mutations in just the cytoplasmic domain.
Figures
Fig. 1
Structure of L1. Normal L1 has 6 Ig domains, 5 fibronectin (FN) type III domains, a short transmembrane region and a 114 amino acid cytoplasmic domain. Class 1 mutations disrupt only the cytoplasmic domain. Class 2 mutations, such as an arginine (R) to glutamine (Q) conversion (37), alter the structure of the extracellular domain. Class 3 mutations result in a stop codon that causes a truncation in the extracellular domain.
Fig. 2
Correlation of class of L1CAM mutation with clinical signs. The percentage of patients with varying degrees of hydrocephalus, survival, mental retardation and presence of adducted thumb are show. Class 1 (1). class 2 (2) and class 3 (3) mutations are defined in the text and illustrated in Figure 1.
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