A Missense Founder Mutation in VLDLR is Associated with Dysequilibrium Syndrome Without Quadrupedal Locomotion

Overview

Journal BMC Med Genet

Publisher Biomed Central

Specialty Genetics

Date 2012 Sep 15

PMID 22973972

Citations 20

Authors

Bassam R Ali

Jennifer L Silhavy

Matthew J Gleeson

Joseph G Gleeson

Lihadh Al-Gazali

Affiliations

Soon will be listed here.

Abstract

Background: Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes.

Methods: SNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used.

Results: We identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function.

Conclusions: We have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.

Citing Articles

The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.

Gariballa N, Mohamed F, Badawi S, Ali B J Biomed Sci. 2024; 31(1):64.

PMID: 38937821 PMC: 11210014. DOI: 10.1186/s12929-024-01054-1.

Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Cavusoglu D, Ozturk G, Turkdogan D, Kurul S, Yis U, Komur M Cerebellum. 2024; 23(5):1950-1965.

PMID: 38622473 PMC: 11489189. DOI: 10.1007/s12311-024-01690-1.

Spectrum of genetic disorders and gene variants in the United Arab Emirates national population: insights from the CTGA database.

Bizzari S, Nair P, Hana S, Deepthi A, Al-Ali M, Al-Gazali L Front Genet. 2023; 14:1177204.

PMID: 37214420 PMC: 10194840. DOI: 10.3389/fgene.2023.1177204.

Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia.

Miterko L, Lin T, Zhou J, van der Heijden M, Beckinghausen J, White J Nat Commun. 2021; 12(1):1295.

PMID: 33637754 PMC: 7910465. DOI: 10.1038/s41467-021-21417-8.

Endoplasmic Reticulum Associated Protein Degradation (ERAD) in the Pathology of Diseases Related to TGFβ Signaling Pathway: Future Therapeutic Perspectives.

Gariballa N, Ali B Front Mol Biosci. 2020; 7:575608.

PMID: 33195419 PMC: 7658374. DOI: 10.3389/fmolb.2020.575608.

References

Turkmen S, Hoffmann K, Demirhan O, Aruoba D, Humphrey N, Mundlos S . Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene. Eur J Hum Genet. 2008; 16(9):1070-4. DOI: 10.1038/ejhg.2008.73. View

Kaya N, Aldhalaan H, Al-Younes B, Colak D, Shuaib T, Al-Mohaileb F . Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII. Am J Med Genet B Neuropsychiatr Genet. 2011; 156B(7):826-34. DOI: 10.1002/ajmg.b.31227. View

Seelow D, Schuelke M, Hildebrandt F, Nurnberg P . HomozygosityMapper--an interactive approach to homozygosity mapping. Nucleic Acids Res. 2009; 37(Web Server issue):W593-9. PMC: 2703915. DOI: 10.1093/nar/gkp369. View

Aridor M . Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases. Adv Drug Deliv Rev. 2007; 59(8):759-81. DOI: 10.1016/j.addr.2007.06.002. View

Tissir F, Goffinet A . Reelin and brain development. Nat Rev Neurosci. 2003; 4(6):496-505. DOI: 10.1038/nrn1113. View

Herz J, Boycott K, Parboosingh J . "Devolution" of bipedality. Proc Natl Acad Sci U S A. 2008; 105(21):E25. PMC: 2396673. DOI: 10.1073/pnas.0802584105. View

Turkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah A, Mischung C . CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 2009; 5(5):e1000487. PMC: 2677160. DOI: 10.1371/journal.pgen.1000487. View

Kolb L, Arlier Z, Yalcinkaya C, Ozturk A, Moliterno J, Erturk O . Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy. Neurogenetics. 2010; 11(3):319-25. DOI: 10.1007/s10048-009-0232-y. View

Hussain M, Strickland D, Bakillah A . The mammalian low-density lipoprotein receptor family. Annu Rev Nutr. 1999; 19:141-72. DOI: 10.1146/annurev.nutr.19.1.141. View

10.

May P, Woldt E, Matz R, Boucher P . The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med. 2007; 39(3):219-28. DOI: 10.1080/07853890701214881. View

11.

Grantham R . Amino acid difference formula to help explain protein evolution. Science. 1974; 185(4154):862-4. DOI: 10.1126/science.185.4154.862. View

12.

Gent J, Braakman I . Low-density lipoprotein receptor structure and folding. Cell Mol Life Sci. 2004; 61(19-20):2461-70. DOI: 10.1007/s00018-004-4090-3. View

13.

Rasmussen F, GUSTAVSON K, Sara V, Floderus Y . The dysequilibrium syndrome: a study of the etiology and pathogenesis. Clin Genet. 1985; 27(2):191-5. DOI: 10.1111/j.1399-0004.1985.tb00210.x. View

14.

Steinlin M . Non-progressive congenital ataxias. Brain Dev. 1998; 20(4):199-208. DOI: 10.1016/s0387-7604(98)00019-9. View

15.

Murray S, Oliphant A, Shen R, McBride C, Steeke R, Shannon S . A highly informative SNP linkage panel for human genetic studies. Nat Methods. 2005; 1(2):113-7. DOI: 10.1038/nmeth712. View

16.

Hoffmann K, Lindner T . easyLINKAGE-Plus--automated linkage analyses using large-scale SNP data. Bioinformatics. 2005; 21(17):3565-7. DOI: 10.1093/bioinformatics/bti571. View

17.

Ozcelik T, Akarsu N, Uz E, Caglayan S, Gulsuner S, Onat O . Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci U S A. 2008; 105(11):4232-6. PMC: 2393756. DOI: 10.1073/pnas.0710010105. View

18.

Siepel A, Bejerano G, Pedersen J, Hinrichs A, Hou M, Rosenbloom K . Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005; 15(8):1034-50. PMC: 1182216. DOI: 10.1101/gr.3715005. View

19.

Humphrey N, Mundlos S, Turkmen S . Genes and quadrupedal locomotion in humans. Proc Natl Acad Sci U S A. 2008; 105(21):E26. PMC: 2396709. DOI: 10.1073/pnas.0802839105. View

20.

Moheb L, Tzschach A, Garshasbi M, Kahrizi K, Darvish H, Heshmati Y . Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. Eur J Hum Genet. 2007; 16(2):270-3. DOI: 10.1038/sj.ejhg.5201967. View