The objective of the study was to report a new disease-causing mutation site of L1CAM, and gain further insight into the pathophysiology of hydrocephalus.
The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus.
In addition, <i>Ccdc39<sup>prh/prh</sup></i> mutants with L1 cell adhesion molecule (<i>L1cam</i>) gene mutation, which causes X-linked human congenital hydrocephalus, showed an accelerated early hydrocephalus phenotype (<i>P</i><0.05-0.01).
Mutations in L1cam, a member of the immunoglobulin (Ig) superfamily that mediate cell-cell contacts through homo- and heterophilic interactions, are associated with several developmental abnormalities of the nervous system, including mental retardation, limb spasticity, hydrocephalus, and corpus callosum aplasia.
Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPβ, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13).
In the present study, we describe a novel L1CAM mutation in a 33-year-old woman reporting two voluntary terminations of pregnancy due to fetal hydrocephalus.
Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission.
To begin to understand how L1cam deficiencies result in hydrocephalus and to identify modifier loci that contribute to X-linked hydrocephalus by genetically interacting with L1cam, we conducted a genome-wide scan on F2 L1-6D mice, bred from L1-6D 129S2/SvPasCrlf and C57BL/6J mice.
The mental deficiency that is common in these patients therefore is likely to be part of the disease (through the L1CAM-FGFR interaction) rather than a consequence of the skull size or of the associated hydrocephalus.
Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (Hydrocephalus as a result of Stenosis of the Aqueduct of Sylvius), MASA (Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked Agenesis of the Corpus Callosum (ACC).
X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders.
We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene.
Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1.
These results provide, for the first time, direct demonstration of the deleterious effects of hydrocephalus/MASA mutations on two intrinsic properties of L1.
L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.