Reduced Blood Levels of Reelin as a Vulnerability Factor in Pathophysiology of Autistic Disorder
Open accessAbstract
1. Autism is a severe neurodevelopmental disorder with potential genetic and environmental etiologies. Recent genetic linkage reports and biochemical analysis of postmortem autistic cerebellum point to Reelin, an important secretory extracellular protein, as being involved in the pathology of autism. 2. We hypothesized that blood levels of Reelin and its isoforms would be altered in autistic twins, and their first degree relatives versus normal controls. 3. We measured blood levels of unprocessed Reelin (410 kDa) and its proteolytic cleavage products (Reelins 330 and 180 kDa) as well as albumin and ceruloplasmin in 28 autistic individuals, their parents (13 fathers, 13 mothers), 6 normal siblings, and 8 normal controls using SDS-PAGE and western blotting. 4. Results indicated significant reductions in 410 kDa Reelin species in autistic twins (-70%, p < 0.01), their fathers (-62%, p < 0.01), their mothers (-72%, p < 0.01), and their phenotypically normal siblings (-70%, p < 0.01) versus controls. Reelin 330 kDa values did not vary significantly from controls. Reelin 180 kDa values for parents (fathers -32% p < 0.05 vs. controls, mothers -34%) declined when compared to controls. In contrast autistic Reelin 180 kDa increased, albeit nonsignificantly versus controls. Albumin and ceruloplasmin values for autistics and their first degree relatives did not vary significantly from controls. There were no significant meaningful correlations between Reelin, albumin and ceruloplasmin levels, age, sex, ADI scores, or age of onset. 5. These results suggest that Reelin 410 deficiency may be a vulnerability factor in the pathology of autism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369 · see citing works
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,841 · see citing works
Lord, C., Rutter, M., & Le Couteur, A. (1994) · Journal of Autism and Developmental Disorders · doi:10.1007/bf02172145 · Cited by 9,065 · see citing works
(1943) · The Nervous child · Cited by 8,870 · see citing works
Autistic disturbances of affective contact.
Kanner, L. (1968) · PubMed · Cited by 2,273 · see citing works
A protein related to extracellular matrix proteins deleted in the mouse mutant reeler
D'Arcangelo, G., G. Miao, G., Chen, S.-C., Scares, H. D., Morgan, J. I., & Curran, T. (1995) · Nature · doi:10.1038/374719a0 · Cited by 1,748 · see citing works
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., & Herz, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80782-5 · Cited by 1,261 · see citing works
Guidotti, A., Auta, J., Davis, J. M., Gerevini, V. D. G., Dwivedi, Y., Grayson, D. R., Impagnatiello, F., Pandey, G. N., Pesold, C., Sharma, R. P., et al. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.11.1061 · Cited by 1,203 · see citing works
A clinicopathological study of autism
Bailey, A. (1998) · Brain · doi:10.1093/brain/121.5.889 · Cited by 1,083 · see citing works
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., & Herz, J. (1999) · Neuron · doi:10.1016/s0896-6273(00)80861-2 · Cited by 916 · see citing works
Ogawa, M., Miyata, T., Nakajimat, K., Yagyu, K., Seike, M., Ikenaka, K., Yamamoto, H., & Mikoshibat, K. (1995) · Neuron · doi:10.1016/0896-6273(95)90329-1 · Cited by 889 · cited 1× · see citing works
“Reelin is a glycoprotein with serine protease activity (Quattrocchi et al., 2002) and a relative molecular mass of »388 kDa, which was discovered simultaneously by Ogawa et al. (1995) and D’Arcangelo et al. (1995).”
BackgroundAutosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations
Hong, S. E., Shugart, Y. Y., Huang, D. T.-C., Shahwan, S. A., Grant, P. E., Hourihane, J. O., Martin, N. D. T., & Walsh, C. A. (2000) · Nature Genetics · doi:10.1038/79246 · Cited by 878 · see citing works
Reelin Is a Ligand for Lipoprotein Receptors
D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., & Curran, T. (1999) · Neuron · doi:10.1016/s0896-6273(00)80860-0 · Cited by 808 · see citing works
A decrease of reelin expression as a putative vulnerability factor in schizophrenia
Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H. J., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15718 · Cited by 753 · see citing works
Reelin Binds α3β1 Integrin and Inhibits Neuronal Migration
Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., & Anton, E. S. (2000) · Neuron · doi:10.1016/s0896-6273(00)00007-6 · Cited by 577 · see citing works
Reelin Is a Secreted Glycoprotein Recognized by the CR-50 Monoclonal Antibody
D’Arcangelo, G., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K., & Curran, T. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-01-00023.1997 · Cited by 515 · see citing works
Fatemi, S. H., Earle, J. A., & McMenomy, T. (2000) · Molecular Psychiatry · doi:10.1038/sj.mp.4000783 · Cited by 447 · see citing works
Self-citationBrainstem, cerebellar and limbic neuroanatomical abnormalities in autism
Courchesne, E. (1997) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(97)80016-5 · Cited by 401 · see citing works
Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder
Persico, A. M., D'Agruma, L., Maiorano, N., Totaro, A., Militerni, R., Bravaccio, C., Wassink, T. H., Schneider, C., Melmed, R., Trillo, S., et al. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000850 · Cited by 337 · see citing works
Proteins of the CNR Family Are Multiple Receptors for Reelin
Senzaki, K., Ogawa, M., & Yagi, T. (1999) · Cell · doi:10.1016/s0092-8674(00)81552-4 · Cited by 272 · see citing works
Microscopic Neuroanatomic Abnormalities in Autism
Bauman, M. L. (1991) · Pediatrics · doi:10.1542/peds.87.5.791 · Cited by 242 · see citing works
The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2
Stockinger, W., Brandes, C., Fasching, D., Hermann, M., Gotthardt, M., Herz, J., Schneider, W. J., & Nimpf, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004119200 · Cited by 239 · cited 1× · see citing works
“Recent work by several laboratories (D’Arcangelo et al., 1995, 1997, 1999; Dulabon et al., 2000; Hiesberger et al., 1999; Senzaki et al., 1999; Stockinger et al., 2000 ) point to multiple proteins as likely receptors for Reelin protein binding.”
BackgroundDysregulation of Reelin and Bcl-2 Proteins in Autistic Cerebellum
Fatemi, S. H., Stary, J. M., Halt, A. R., & Realmuto, G. R. (2001) · Journal of Autism and Developmental Disorders · doi:10.1023/a:1013234708757 · Cited by 212 · see citing works
Self-citationRodríguez, M. Á., Pesold, C., Liu, W. S., Kriho, V., Guidotti, A., Pappas, G. D., & Costa, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050589797 · Cited by 178 · see citing works
Smalheiser, N. R., Costa, E., Guidotti, A., Impagnatiello, F., Auta, J., Lacor, P., Kriho, V., & Pappas, G. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.3.1281 · Cited by 158 · see citing works
Scrambler, a new neurological mutation of the mouse with abnormalities of neuronal migration
Sweet, H. O., Bronson, R. T., Johnson, K. R., Cook, S. A., & Davisson, M. T. (1996) · Mammalian Genome · doi:10.1007/s003359900240 · Cited by 155 · see citing works
Reelin Is a Serine Protease of the Extracellular Matrix
Quattrocchi, C. C., Wannenes, F., Persico, A. M., Ciafré, S. A., D'Arcangelo, G., Farace, M. G., & Keller, F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106996200 · Cited by 154 · see citing works
Fatemi, S. H. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000129 · Cited by 151 · see citing works
Self-citationAltered levels of Reelin and its isoforms in schizophrenia and mood disorders
Fatemi, S. H., Kroll, J., & Stary, J. M. (2001) · Neuroreport · doi:10.1097/00001756-200110290-00014 · Cited by 149 · see citing works
Self-citationYoneshima, H., Nagata, E., Matsumoto, M., Yamada, M. K., Nakajima, K., Miyata, T., Ogawa, M., & Mikoshiba, K. (1997) · Neuroscience Research · doi:10.1016/s0168-0102(97)00088-6 · Cited by 143 · see citing works
Identification of Reelin-induced Sites of Tyrosyl Phosphorylation on Disabled 1
Keshvara, L. M., Benhayon, D., Magdaleno, S. M., & Curran, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101422200 · Cited by 137 · see citing works
Grant, S. G. N., Karl, K. A., Kiebler, M. A., & Kandel, E. R. (1995) · Genes & Development · doi:10.1101/gad.9.15.1909 · Cited by 136 · see citing works
Rodríguez, M. Á., Pesold, C., Liu, W. S., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3550 · Cited by 119 · see citing works
Lacor, P. N., Grayson, D. R., Auta, J., Sugaya, I., Costa, E., & Guidotti, A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050589597 · Cited by 110 · see citing works
Lacor, P. N., Grayson, D. R., Auta, J., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3556 · Cited by 80 · see citing works
Robinson, C., Shore, R. F., Bonass, W. A., et al. (1998) · Caries Research · doi:10.1159/000016452 · Cited by 54 · see citing works
Diagnostic criteria for primary progressive mutiple sclerosis: a position paper.
(2000) · Pure Amsterdam UMC · doi:10.1002/1531-8249(200006)47:6 · Cited by 2 · see citing works
Rodier (1996) · doi:10.1002/(sici)1096-9861(19960624)370:2
Flagged first, then by citations
Research works printed but not linked: 1
- Berg, D., Weishaupt, A., Francis, M. J., Miura, N., Yang, X. L., Goodyer, I.D., Naumann, M., Koltzenburg, M., Reiners, K., and Becker, G. (2000). Changes of copper-transporting proteins and ceruloplasmin in the centiform nuclei in primary adult-onset dystonia. Ann. Neurol.47:827–830. [PubMed] [Google Scholar]
Cited by
Sorted by citations
Maternal immune activation and abnormal brain development across CNS disorders
Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., Toovey, S., & Prinssen, E. P. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.187 · Cited by 880 · see citing works
Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
Self-citationThe genetics of autistic disorders and its clinical relevance: a review of the literature
Freitag, C. M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001896 · Cited by 638 · see citing works
Searching for ways out of the autism maze: genetic, epigenetic and environmental clues
Persico, A. M., & Bourgeron, T. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.05.010 · Cited by 575 · see citing works
The involvement of Reelin in neurodevelopmental disorders
Folsom, T. D., & Fatemi, S. H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.015 · Cited by 275 · see citing works
Self-citationFatemi, S. H., Folsom, T. D., Kneeland, R. E., & Liesch, S. B. (2011) · The Anatomical Record · doi:10.1002/ar.21299 · Cited by 137 · see citing works
Self-citationHLA-DR4 as a Risk Allele for Autism Acting in Mothers of Probands Possibly During Pregnancy
Johnson, W. G., Buyske, S., Mars, A. E., Sreenath, M., Stenroos, E. S., Williams, T. A., Stein, R., & Lambert, G. H. (2009) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpediatrics.2009.74 · Cited by 77 · see citing works
Methodological factors influencing measurement and processing of plasma reelin in humans
Lugli, G., Krueger, J. M., Davis, J. M., Persico, A. M., Keller, F., & Smalheiser, N. R. (2003) · BMC Biochemistry · doi:10.1186/1471-2091-4-9 · Cited by 60 · see citing works
Polymorphic GGC repeat differentially regulates human reelin gene expression levels
Persico, A. M., Levitt, P., & Pimenta, A. F. (2006) · Journal of Neural Transmission · doi:10.1007/s00702-006-0441-6 · Cited by 52 · see citing works
Polymorphisms of candidate genes in Slovak autistic patients
Kelemenova, S., Schmidtova, E., Ficek, A., Celec, P., Kubranska, A., & Ostatnikova, D. (2010) · Psychiatric Genetics · doi:10.1097/ypg.0b013e32833a1eb3 · Cited by 50 · see citing works
Between Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?
Suprunowicz, M., Tomaszek, N., Urbaniak, A., Zackiewicz, K., Modzelewski, S., & Waszkiewicz, N. (2024) · Nutrients · doi:10.3390/nu16040549 · Cited by 44 · see citing works
Camacho, J., Ejaz, E., Ariza, J., Noctor, S. C., & Martínez-Cerdeño, V. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.07.031 · Cited by 25 · see citing works
- Authors
- Fatemi, S. H., Stary, J. M., & Egan, E. A.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Fatemi, S. Hossein
- ORCID
- Fatemi, S. Hossein
- Venue
- Cellular and Molecular Neurobiology
- Published
- 2002-04
- Volume
- 22
- Issue
- 2
- Pages
- 139-152
- ISSN
- 0272-4340 (ISSN-L)
- 1573-6830
- PMC
- PMC11533798
- OpenAlex
- W1503707236
- Cited by
- 122
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 10 · 2014: 6 · 2013: 7 · 2012: 7
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Cellular and Molecular Neurobiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- reelin, autism spectrum disorder, first-degree relatives, vulnerability factors, cerebellum, albumin, ceruloplasmin, neurodevelopmental disorders
- MeSH terms
- Reelin Protein, Adult, Age Factors, Autistic Disorder, Cerebellum, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Testing, Humans, Male, Middle Aged, Molecular Weight, Nerve Tissue Proteins, Polymorphism, Genetic, Serine Endopeptidases, Sex Factors, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Twin Studies as Topic, Genetic Predisposition to Disease, Protein Isoforms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
