Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome

Abstract

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2 -24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C4T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy

“…The compound heterozygous mutation, composed of a missense mutation in exon 11 and a frameshift mutation in exon 12. Thus, it has been concluded that a truncated VLDRL protein can serve as the sole genetic predecessor in DES [20,21,34], with our findings providing additional support.…”

“…Thus, it was unclear whether an isolated mutation in VLDRL could explain the syndrome in its entirety. Follow-up studies in an Iranian family with DES subsequently revealed a homozygous nucleotide substitution in exon 10 resulting in a premature stop codon in the VLDLR gene [20].…”

“…Structural examination of the gene and the defective protein has not revealed any identifiable portion that appears to be responsible for quadrupedal gait [21,40]. A stop codon in exon 5 and a frameshift mutation in exon 17 both lead to quadrupedal gait in Turkish families with congenital ataxia and cerebellar hypoplasia [37], whereas a stop codon in exon 10 [20], the recent compound heterozygous mutation affecting exons 11 and 12 [36], and our report of a deletion affecting exons 1-5 resulted in patients with similar neurological findings and bipedal, ataxic gait. Based on these findings, we posit quadrupedal and bipedal gait are different manifestations of the same genetic syndrome and represent a spectrum of symptomatic disease resulting from various VLDLR mutations.…”

“…More recently, mutations in the Very Low Density Lipoprotein Receptor (VLDLR) have been identified in patients of Turkish [18,19], Iranian [20], and Hutterite [21] descent with non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance [22,23]. Such neurological sequelae can be explained by the intricate role of the VLDLR protein in the Reelin signaling pathway, which is important in cerebellogenesis [21].…”

Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene

“…The LDLR gene family comprises a group of structurally related multifunctional cell-surface receptors (VLDLR, apolipoprotein E receptor 2 (ApoER2), the LDL receptor, LRP and Megalin) that mediates endocytosis of extracellular ligands. 9 All members are characterised by common structural features that include (1) cysteine-rich repeats consisting of 40 amino-acid residues in the ligand-binding domain or in the complement-type domain; (2) epidermal growth factor precursortype repeats; (3) module of 50 amino-acid residues with a consensus tetrapeptide, YWTD; (4) a single transmembrane domain; and (5) a cytoplasmic domain containing an NPXY sequence required for clustering of the receptor into coated pits. 10 VLDLR is part of the RELN signalling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum.…”