HGNC Approved Gene Symbol: VLDLR
Cytogenetic location: 9p24.2 Genomic coordinates (GRCh38): 9:2,621,787-2,660,056 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p24.2 | Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome 1 | 224050 | Autosomal recessive | 3 |
On isolating and characterizing cDNAs encoding human very low density lipoprotein (VLDL) receptor, Sakai et al. (1994) found 2 isoforms, one consisting of 5 domains that resembles the low density lipoprotein receptor (606945), and a variant form lacking an O-linked sugar domain. The 5-prime untranslated region of the receptor mRNA contains a polymorphic triplet repeat that is also found in the FMR1 gene (309550) in the fragile X syndrome (300624). The VLDL receptor has a ligand specificity and tissue distribution different from those of the LDL receptor (LDLR; 606945).
VLDLR, like LDLR, consists of 5 domains: an N-terminal 328 amino acids composed of 8 cysteine-rich repeats homologous to the ligand-binding domain of LDLR; a 396-amino acid region homologous to the epidermal growth factor precursor that mediates the acid-dependent dissociation of the ligand in the LDLR; a 46-amino acid domain homologous to the clustered O-linked sugars of the LDLR; a 22-amino acid transmembrane domain; and a 54-amino acid cytoplasmic domain including an NPXY sequence that is required for clustering of the receptor into coated pits. The gene for the VLDL receptor is highly expressed in heart, muscle, and adipose tissues, which are active in fatty acid metabolism; essentially no expression is found in liver. VLDLR appears to play a crucial role in triglyceride metabolism. Oka et al. (1994) cloned a cDNA for VLDLR from a human heart cDNA library. A mature protein of 846 amino acids, preceded by a 27-residue signal peptide, shares 97% amino acid sequence identity with rabbit VLDLR. A tetrapeptide NPVY that potentially serves as a signal for clustering of the VLDLR on coated pits was present in the cytoplasmic domain, which is 100% conserved between human and rabbit. Gafvels et al. (1994) cloned cDNA for the mouse homolog of VLDLR, deduced the amino acid sequence of the protein, and by Northern hybridization demonstrated that the VLDLR mRNA is most abundant in skeletal muscle, heart, kidney, and brain.
Sakai et al. (1994) determined that the VLDLR gene contains 19 exons spanning approximately 40 kb. The exon-intron organization of the gene is almost identical to that of the LDLR gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor.
By PCR analysis of DNA from human-rodent hybrid cells, Sakai et al. (1994) mapped the VLDLR gene to chromosome 9. By fluorescence in situ hybridization using the cloned cDNA as a hybridization probe, Oka et al. (1994) localized the VLDLR gene to 9p23. Naggert and Mu (1994) showed that the mouse Vldlr gene maps to chromosome 19. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Vldlr gene to mouse chromosome 19. The assignment of Snf2l2 to the same chromosome defined a new region of synteny between mouse chromosome 19 and the proximal portion of human 9p.
Using in vitro binding experiments, Hiesberger et al. (1999) showed that Reln (600514) binds directly and specifically to the extracellular domains of Vldlr and ApoER2 (602600). Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 (603448) tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons.
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR), a coordinated series of cellular events that increases the capacity of the ER to process the unfolded proteins and reduce the protein loads. Using microarray analysis, Dombroski et al. (2010) found that VLDLR and INHBE (612031) were among hundreds of genes upregulated by ER stress in immortalized human B cell lines. Their expression was also induced by ER stress in primary human fibroblasts, and the expression of VLDLR was induced by ER stress in keratinocytes, which do not express INHBE. The expression of many genes showed individual variation; however, both INHBE and VLDLR were consistently upregulated by ER stress in all 60 immortalized B cell lines examined.
Senturk et al. (2011) showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (600527) or Efnb3 (602297)) and triple Efnb1 (300035)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, Senturk et al. (2011) showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1, which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Senturk et al. (2011) concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system.
Cerebellar Ataxia, Impaired Intellectual Development, and Dysequilibrium Syndrome 1
An autosomal recessive syndrome of nonprogressive cerebellar ataxia and impaired intellectual development is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population (CAMRQ1; 224050). Boycott et al. (2005) used an identity-by-descent mapping approach in 8 patients from 3 interrelated Hutterite families and localized the gene for this syndrome to 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. Within this interval, Boycott et al. (2005) found a 199-kb homozygous deletion encompassing the entire VLDLR gene (192977.0001) in all affected individuals. VLDLR is part of the reelin (RELN; 600514) signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Boycott et al. (2005) proposed that this Hutterite disorder should be referred to as VLDLR-associated cerebellar hypoplasia. It appeared to represent the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect, the other being the form of lissencephaly syndrome (257320) due to mutations in the RELN gene.
In affected members of 2 unrelated Turkish families with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion, previously reported by Tan, 2008 and Tan et al., 2008, respectively, Ozcelik et al. (2008) identified 2 different homozygous mutations in the VLDLR gene (192977.0002 and 192977.0003, respectively). The findings suggested that reelin and VLDLR are important for proper cerebellar development, which plays a large role in gait.
Valence et al. (2016) identified homozygous or compound heterozygous mutations in the VLDLR gene (192977.0007-192977.0011) in 4 patients from 3 families with CAMRQ1. Valence et al. (2016) noted that the combination of an extremely hypoplastic vermis with absent folia and cortical anomalies was strongly suggestive of a defect in the reelin pathway.
Associations Pending Confirmation
A specific isoform of apolipoprotein E (107741), encoded by the APOE4 allele, is associated with the accelerated rate of disease expression of sporadic Alzheimer disease (AD) and late-onset familial AD. Okuizumi et al. (1995) noted that, in patients who carry the APOE4 allele, an earlier age of onset has also been demonstrated in patients who also have mutations in the amyloid precursor protein gene (104760) involving codon 717 (104760.0002) and codons 670 and 671 (104760.0008). On the other hand, the presence of the APOE4 allele makes no difference in familial AD patients with APP692 (104760.0005) or APP693 mutations, nor does it make a difference in chromosome 14-linked familial AD patients (AD3; 607822). Hypothesizing that receptors for APOE-containing lipoproteins act as a potential risk factor for AD, Okuizumi et al. (1995) performed an association study using a polymorphic triplet (CGG) repeat in the VLDLR gene. The frequency of the 5-repeat allele was significantly higher in all Japanese sporadic AD patients (P less than 0.02) than in Japanese controls. Moreover, the odds ratio (OR) was significantly increased in the AD patients homozygous for the 5-repeat allele; OR = 2.1, 95% confidence interval = 1.1-4.2. Multiple logistic regression analysis showed that the relative risk conferred by the presence of 2 copies of the 5-repeat allele and at least 1 copy of the APOE4 allele is 8.7; 95% CI = 2.9-25.8. Okuizumi et al. (1995) concluded that VLDLR is a susceptibility gene for AD.
In a population study of 221 subjects with dementia compared with 249 controls, Helbecque et al. (2001) found that the presence of the VLDLR 5-repeat allele was associated with an increased relative risk of dementia (OR = 1.9). The risk was more pronounced in individuals who also had cardiovascular problems (OR = 2.5) or who carried the APOE4 allele (OR = 8.4). In a clinical study of 124 patients with dementia compared with 179 neuropathologically defined controls, the OR of developing dementia when bearing at least 1 VLDLR 5-repeat allele was 8.1, and was more pronounced in subjects with mixed or vascular dementia than in patients with AD. APOE4 conferred a higher risk of AD than of vascular or mixed dementia. Helbecque et al. (2001) concluded that carrying a VLDLR 5-repeat allele is a risk factor for vascular dementia in individuals with a history of vascular disease, whereas carrying the APOE4 allele is associated with dementia in others. In general, the results suggested the influence of vascular risk factors in the occurrence of dementia.
Layering of neurons in the cerebral cortex and cerebellum requires reelin (RELN; 600514), an extracellular matrix protein, and mammalian disabled (DAB1; 603448), a cytosolic protein that activates tyrosine kinases. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, VLDLR and apolipoprotein E receptor-2 (APOER2; 602600), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1.
Li et al. (2007) characterized biochemical alterations in the retinas of Vldlr knockout mice in an animal model of retinal angiomatous proliferation. Expression of the angiogenic factors vascular endothelial growth factor (VEGF; 192240) and basic fibroblast growth factor (BFGF; 134920) was significantly greater in the area of retinal neovascularization. Mueller cells around the lesion were activated, as indicated by increased expression of glial fibrillary acidic protein (GFAP; 137780). Expression of the proinflammatory cytokine IL18 (600953) and the inflammation mediator intercellular adhesion molecule-1 (ICAM1; 147840) was increased before significant intraretinal neovascularization. Furthermore, phosphorylation of Akt (164730) and mitogen-activated protein kinase (see 176948) and translocalization of nuclear factor kappa-B (see 164011) were greater in Vldlr knockout mouse retinas. Thus, Li et al. (2007) concluded that an inflammatory process was involved in the development of neovascularization in the Vldlr knockout mouse retina.
Boycott et al. (2005) found that the autosomal recessive syndrome of nonprogressive ataxia and impaired intellectual development associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification occurring in the Hutterite population (CAMRQ1; 224050) is due to deletion of the VLDLR gene.
In affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; 224050), Ozcelik et al. (2008) identified a homozygous 769C-T transition in exon 5 of the VLDLR gene, resulting in an arg257-to-ter (R257X) substitution in the ligand-binding domain. Because the mutation is located in the extracellular region, the protein cannot be inserted into the cell membrane to function as a receptor.
In 3 affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; 224050), Ozcelik et al. (2008) identified a homozygous 1-bp deletion (2339delT) in exon 17 of the VLDLR gene, resulting in a frameshift and premature termination in the O-linked sugar domain of the protein. Because the mutation is located in the extracellular region, the protein could not be inserted into the cell membrane to function as a receptor.
Turkmen et al. (2008) identified homozygosity for the 2339delT deletion in 3 affected members of another Turkish family with cerebellar hypoplasia and impaired intellectual development with quadrupedal locomotion. Turkmen et al. (2008) postulated nonsense-mediated mRNA decay.
In affected members of a consanguineous Iranian family with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; 224050), Moheb et al. (2008) identified a homozygous 1342C-T transition in exon 10 of the VLDLR gene, resulting in an arg448-to-ter (R448X) substitution affecting both isoforms. Affected individuals had either no speech at all or spoke only a few words, and none could walk independently. Brain imaging was not performed.
In 2 sibs, born of consanguineous Turkish parents, with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; 224050), Dixon-Salazar et al. (2012) identified a homozygous 7-bp deletion in the VLDLR gene (c.1247_53delGTTACAA), resulting in a frameshift and premature termination (Tyr417fsTer434). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 200 controls. The patients had microcephaly, nystagmus, mild spasticity, arachnodactyly, and pontocerebellar hypoplasia on brain imaging. The patients were initially reported as having pontocerebellar hypoplasia (Dilber et al., 2002), but exome sequencing yielded the correct diagnosis. (Gleeson (2014) provided the correct protein change caused by this mutation, which was erroneously stated in the article by Dixon-Salazar et al. (2012) as p.G1246fsX1305.)
In 5 patients from 2 Omani families with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Ali et al. (2012) identified a homozygous c.2117G-T transversion in exon 15 of the VLDLR gene, resulting in a cys706-to-phe (C706F) substitution at a highly conserved residue in the extracellular EGF-like-3 domain that is predicted to be involved in a cysteine bond. Ali et al. (2012) suggested that the mutation would result in protein misfolding, possible degradation, and loss of function. The mutation was not found in over 1,000 ethnically matched control exomes or in a control database. Haplotype analysis indicated a founder effect. The patients had classic features of the disorder, including delayed psychomotor development, hypotonia, mental retardation, lack of speech development, gait and truncal ataxia, cerebellar hypoplasia, and simplified cortical gyri.
In 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified compound heterozygous mutations in the VLDLR gene: an arg301-to-ter (R301X) substitution on one allele and a c.820+1G-A (192977.0008) mutation, predicted to result in abnormal splicing of exon 54, on the other allele. The splice mutation was found in cis with an arg301-to-gln (R301Q) variant, the pathogenicity of which was unknown. Each parent was heterozygous for one of the mutations.
For discussion of the c.820+1G-A mutation in the VLDLR gene, predicted to result in abnormal splicing of exon 54, that was identified in compound heterozygous state in 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050) by Valence et al. (2016), see 192977.0007.
In a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified compound heterozygous mutations in the VLDLR gene: a trp50-to-ter (W50X) substitution and a glu654-to-gly (E654G; 192977.0010) substitution. The mutations were identified by sequencing of the VLDLR gene; the parents were not tested for the mutations. The D654G mutation was not present in the dbSNP, ExAC, and ESP variant databases.
For discussion of the glu654-to-gly (E654G) substitution in the VLDLR gene that was identified in compound heterozygous state in a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050) by Valence et al. (2016), see 192977.0009.
In a patient (patient 5) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified homozygosity for a trp575-to-ter (W575X) mutation in the VLDLR gene. The mutation, which was identified by sequencing of the VLDLR gene, was present in heterozygous state in the parents.
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