VLDLR – Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome 1

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (CAMRQ1) is an autosomal recessive neurodevelopmental disorder characterized by non-progressive cerebellar hypoplasia, truncal ataxia, and intellectual disability. Onset is in early childhood with delayed ambulation, hypotonia, and cognitive impairment. CAMRQ1 has been mapped to variants in the VLDLR gene encoding the very low-density lipoprotein receptor involved in Reelin signaling.

In the initial report, two unrelated consanguineous Omani families presented affected individuals with cerebellar hypoplasia, moderate intellectual disability, delayed ambulation, and truncal ataxia. Two probands were homozygous for a VLDLR variant, with parents as heterozygous carriers, confirming autosomal recessive inheritance ([PMID:22973972]).

Sequencing identified a shared homozygous missense founder mutation c.2117G>T (p.Cys706Phe) in NM_003383.5, affecting a highly conserved residue and predicted damaging by multiple algorithms ([PMID:22973972]). No additional affected relatives were reported, and the variant segregated with disease in both families.

Functional assays using site-directed mutants in cultured cell lines demonstrated that c.2117G>T (p.Cys706Phe) and other DES-associated missense variants (p.Asp521His, p.Asp487Tyr) cause defective intracellular trafficking, endoplasmic reticulum retention, and failure to reach the plasma membrane for Reelin binding ([PMID:25173816]).

Further studies revealed that ER-retained VLDLR mutants aggregate, elicit ER stress through calnexin association, interact with the ER degradation adaptor SEL1L, and undergo proteasomal degradation, confirming a loss-of-function mechanism via impaired Reelin receptor processing ([PMID:29371607]).

Collectively, biallelic VLDLR missense variants disrupt receptor trafficking in the Reelin pathway, leading to CAMRQ1. VLDLR sequencing should be prioritized in patients with autosomal recessive cerebellar hypoplasia and intellectual disability. Key take-home: VLDLR missense variants causing ER retention and degradation underlie dysequilibrium syndrome type 1.

References

• BMC medical genetics • 2012 • A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion. PMID:22973972
• Biochimica et biophysica acta • 2014 • Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome. PMID:25173816
• Scientific reports • 2018 • Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome. PMID:29371607

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