The genes for all members of the LDL receptor gene family shown in have been disrupted in the mouse. Aside from the LDL receptor, where mutations cause familial hypercholesterolemia (FH), confirmed human gene defects have so far only been identified in LRP2 (a.k.a. Megalin) and VLDLR, while a sequence variant that is associated with coronary artery disease and myocardial infarction has been found in LRP8 [31
]. Defects in LRP2 are the cause for Donnai-Barrow syndrome, a congenital malformation that includes agenesis of the corpus callosum, diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay [32
]. The defects seen in these patients are similar, but not identical to those seen in C57BL/6 × 129 hybrid LRP2 deficient mice, indicating that genetic modifiers influence the relative developmental importance of this large ApoE receptor between different mammalian species and between different mouse strain backgrounds over a wide range.
VLDLR-deficiency in humans was first identified by Boycott et al. [34
] in the Canadian Hutterite population by a combination of a gene mapping and candidate gene approach. Conversely to LRP2 deficiency, this fully autosomal recessive gene defect manifests itself also with a similar, but more severe phenotype in humans compared to the mouse. While the latter present with relatively mild cerebellar hypoplasia and primarily rostral cerebellar malformation with no recognizable ataxia, humans lacking VLDLR show severe cerebellar vermial hypolasia, accompanied by delayed motoric development and persistent truncal ataxia. Additional genetically distinct mutations in human VLDLR have been reported in independent pedigrees in Middle Eastern populations [35
]. Neuroanatomically, the affected patients are indistinguishable from the initially reported Hutterites. By contrast, considerable variations between the two geographically separated populations, but also between individuals, are seen with respect to motor development. Several, but not all, affected individuals of a large Turkish pedigree were reported to be habitually quadrupedal, prompting the authors to attribute VLDLR as a crucial gene for the evolution of bipedal gait [36
]. This conclusion has been drawn into question, however, since even within the same families this behavioral phenotype is not penetrant and the presence of adverse environmental and societal conditions offer far simpler and straightforward explanations [38
Recently, the first compound heterozygous case has been reported in a young child with developmental delay [40
] where loss of VLDLR function is caused by two novel and genetically independent mutations in the VLDLR extracellular domain, resulting in premature translational truncation of the gene product from one allele and a missense mutation in the other, which matches a known FH causing mutation in LDLR, mostly likely through ER retention and degradation of the misfolded protein.
Other human autosomal recessive defects with phenotypes that are virtually identical, but non-allelic to, VLDLR deficiency have also been reported [36
]. One of these loci has been narrowed to a short minimal region on Chr. 17 [37
]. This region contains Crk, a downstream component of the Reelin signaling pathway [3
] (), prompting Boycott et al. [40
] to propose Crk as a highly likely candidate gene for the Chr. 17 defect.
SORL1 (a.k.a. LR11) is an LDL receptor family member that combines most of the structural features of the core family members () with functional domains found in other not related proteins, most notably a vacuolar protein sorting (VPS) domain [41
]. Some of the in vivo functions of SORL1 resemble those of LRP1, in particular with respect to its role in regulating the trafficking of APP and as a signal modulator in the vascular wall, where it regulates AngII dependent smooth muscle cell migration [42
]. SORL1 expression is dramatically reduced in the brains of AD patients [28
] and intronic variants within SORL1 are genetically associated with AD [43
]. Postmortem expression analysis also showed a statistically significant inverse correlation between SORL1 expression and cognitive impairment, suggesting SORL1 expression as a marker for prodromal AD [44
]. Intriguingly, docosahexanoic acid, an essential omega-3 fatty acid, increases SORL1 expression in vitro and in mice in vivo [45
], providing a potential mechanism for a role of diet in AD prevention.
LRP6 is a 'distant' member of the LDL receptor gene family and functions as an obligate component of the Wnt signaling complex at the plasma membrane which also includes Frizzled (Fz) receptors. A particular LRP6 variant (Ile1062Val) has previously been shown to have decreased canonical Wnt signaling associated with reduced bone mass. The same variant was found to convey an increased risk for late-onset AD in an ApoE4 dependent manner suggesting a role for Wnt signaling in AD pathogenesis [46