Alternative titles; symbols
HGNC Approved Gene Symbol: CRADD
Cytogenetic location: 12q22 Genomic coordinates (GRCh38) : 12:93,677,375-93,894,840 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q22 | Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly | 614499 | Autosomal recessive | 3 |
The CRADD gene encodes an adaptor protein required for activation of caspase-2 (CASP2; 600639)-mediated apoptosis (summary by Di Donato et al., 2016).
Caspases are a family of cysteine proteases related to ICE (147678) and represent the effector arm of the cell death pathway. In metazoan cells, caspases exist as inactive polypeptide precursors (zymogens), each of which is composed of a large and small catalytic subunit and a prodomain, which is cleaved to activate the protease. Adaptor molecules containing protein-protein interaction motifs are thought to mediate the coupling of these death proteases to signaling pathways. Duan and Dixit (1997) isolated cDNAs encoding such an adaptor molecule, which they designated RAIDD (RIP-associated ICH1/CED3-homologous protein with a death domain). The predicted 199-amino acid protein contained an N-terminal domain (NTD) homologous to the prodomain of ICH1 (CASP2; 600639) and a death domain (DD) similar to that found in RIP (603453). The NTD mediated the binding of RAIDD to ICH1 in vitro and in vivo. RAIDD specifically bound RIP, but not the DD-containing receptors FAS (134637) or TNFR1 (191190), or the DD-containing receptor-associated proteins FADD (602457) or TRADD (603500). However, coimmunoprecipitation studies indicated that TNFR1 complexed with RAIDD in the presence of TRADD and RIP, and through RAIDD, ICH1 was recruited to the signaling complex. Overexpression of RAIDD in mammalian cells induced apoptosis. Duan and Dixit (1997) concluded that RAIDD can function as an adaptor molecule in recruiting the death protease ICH1 to the TNFR1 signaling complex. Northern blot analysis revealed that RAIDD is expressed ubiquitously as a 1.35-kb mRNA. Independently, Ahmad et al. (1997) cloned cDNAs encoding RAIDD, which they called CRADD for 'caspase and RIP adaptor with death domain.' Using in vitro binding studies, they found that CRADD interacted specifically with RIP and CASP2.
Tinel and Tschopp (2004) showed that activation of caspase-2 occurs in a complex that contains the death domain-containing protein PIDD (605247), whose expression is induced by p53 (191170), and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli. Because PIDD functions in p53-mediated apoptosis, Tinel and Tschopp (2004) concluded that the complex assembled by PIDD and caspase-2 is likely to regulate apoptosis induced by genotoxins.
Horvat and Medrano (1998) analyzed clones spanning the region of mouse chromosome 10 deleted in mutant 'high growth' (hg) mice. They found that this deletion spans approximately 500 kb and includes the mouse Raidd gene.
By analysis of a radiation hybrid panel, Horvat and Medrano (1998) mapped the human RAIDD gene to 12q21.33-q23.1.
By homozygosity mapping followed by exome sequencing of 5 Mennonite patients with autosomal recessive intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Puffenberger et al. (2012) identified a homozygous mutation in the CRADD gene (G128R; 603454.0001). Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)
In 2 sibs with MRT34 with variant lissencephaly from the same Pennsylvania Mennonite population studied by Puffenberger et al. (2012), Di Donato et al. (2016) identified the same homozygous G128R mutation in the CRADD gene. The mutation was found by whole-exome sequencing. Sanger sequencing of the CRADD gene in 18 individuals with the 'thin' variant of lissencephaly identified 3 additional patients from 2 unrelated families with homozygous missense mutations (603454.0002-603454.0003) and 1 patient who was compound heterozygous for a missense mutation (603454.0004) and a deletion of 12q22 that included the CRADD gene. In vitro functional expression studies showed that only 1 of the missense mutations (G128R) resulted in an unstable protein and decreased PIDD binding; the remaining mutations did not disrupt PIDD or CASP2 binding and did not lead to decreased amounts of the mutant protein. However, the mutant proteins were unable to induce apoptosis when expressed in neuronal cells due to an inability to activate CASP2, despite normal binding to CASP2. Wildtype CRADD induced cell death in neuronal cells. The findings indicated that the mutations caused a loss of function, and suggested that the cortical malformations observed result from reduced apoptosis rather than from a neuronal migration disorder. Di Donato et al. (2016) concluded that CRADD/CASP2 plays a role in synaptic plasticity and cortical architecture during mammalian brain development. Targeted panel sequencing in another 148 individuals with lissencephaly in whom molecular testing had excluded mutations in known lissencephaly-associated genes did not identify additional CRADD mutations.
In 22 patients with MRT34 from 15 Finnish families, Polla et al. (2019) identified homozygosity for the R170H mutation in the CRADD gene (603454.0003) that had previously been identified in a Finnish woman with MRT34 by Di Donato et al. (2016). The allele frequency in the Finnish population was noted to be 0.59%, substantially higher than that of the European non-Finnish population (0.01%). The variant frequency was even higher in eastern and northern parts of Finland (1.25%). A genealogic study of the affected Finnish families revealed that 50% of the grandparents originated from northeastern Finland, indicating a founder effect.
Di Donato et al. (2016) found that Cradd-null mice had enlarged brain and head sizes, but normal layering of the cerebral cortex. About 26% of mice developed seizures.
In 5 Mennonite patients with autosomal recessive intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Puffenberger et al. (2012) identified a homozygous 382G-C transversion in the CRADD gene, resulting in a gly128-to-arg (G128R) substitution in a highly conserved residue in the CRADD death domain. The mutation was found by homozygosity mapping followed by exome sequencing. Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) Overexpression of mutant murine Cradd with the G128R mutation showed normal protein localization to the nucleus and cytoplasm. However, when co-overexpressed with wildtype Pidd (605247), mutant G128R Cradd formed large cytoplasmic aggregates with a relative loss of Cradd expression in the nucleus. The findings suggested that the G128R mutation alters 1 of the interaction surfaces of the CRADD death domain to decrease affinity for the PIDD death domain.
In 2 Mennonite sisters (family LR04-101) with MRT34 with thin lissencephaly, Di Donato et al. (2016) identified homozygosity for the same c.382G-C transversion (rs387906861) in the CRADD gene that had been identified in a Mennonite family (LR15-293) by Puffenberger et al. (2012). The mutation, which was found by whole-exome sequencing, was present at a low frequency in the ExAC database (0.000008).
In 2 sibs from a consanguineous Turkish family (LR05-279) with intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Di Donato et al. (2016) identified a homozygous c.508C-T transition (c.508C-T, NM_003805.3) in the CRADD gene, resulting in an arg170-to-cys (R170C) substitution at a highly conserved residue in the death domain. The mutation, which was found by Sanger sequencing, was present at a low frequency in the ExAC database (0.0000083).
In a 51-year-old Finnish woman (LR00-150) with intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Di Donato et al. (2016) identified a homozygous c.509G-A transition (rs141179774) in the CRADD gene, resulting in an arg170-to-his (R170H) substitution at a highly conserved residue in the death domain. The mutation, which was found by Sanger sequencing, was present at a low frequency in the European (Finnish) population (0.006665) as well as in the total population (0.0005277) in the ExAC database.
In 22 patients with MRT34 from 15 Finnish families, Polla et al. (2019) identified homozygosity for the R170H mutation. The authors stated that the allele frequency in the Finnish population was 0.59%, substantially higher than that of the European non-Finnish population (0.01%). The variant frequency was even higher in eastern and northern parts of Finland (1.25%). A genealogic study of the affected Finnish families revealed that 50% of the grandparents originated from northeastern Finland, indicating a founder effect.
In an 18-year-old man of western European origin (LR02-006) with intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Di Donato et al. (2016) identified compound heterozygosity for a c.491T-G transversion (rs370916968) in the CRADD gene, resulting in a phe164-to-cys (F164C) substitution at a highly conserved residue in the death domain, and a 3.07-Mb deletion (chr12:92,443,579_95,515,465, GRCh38) of chromosome 12q22 including the CRADD gene. The point mutation, which was found by Sanger sequencing, was present at a low frequency in the ExAC database (0.00002496).
Ahmad, M., Srinivasula, S. M., Wang, L., Talanian, R. V., Litwack, G., Fernandes-Alnemri, T., Alnemri, E. S. CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer Res. 57: 615-619, 1997. [PubMed: 9044836]
Di Donato, N., Jean, Y. Y., Maga, A. M., Krewson, B. D., Shupp, A. B., Avrutsky, M. I., Roy, A., Collins, S., Olds, C., Willert, R. A., Czaja, A. M., Johnson, R., and 16 others. Mutations in CRADD result in reduced caspase-2-mediated neuronal apoptosis and cause megalencephaly with a rare lissencephaly variant. Am. J. Hum. Genet. 99: 1117-1129, 2016. [PubMed: 27773430] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.010]
Duan, H., Dixit, V. M. RAIDD is a new 'death' adaptor molecule. Nature 385: 86-89, 1997. [PubMed: 8985253] [Full Text: https://doi.org/10.1038/385086a0]
Horvat, S., Medrano, J. F. A 500-kb YAC and BAC contig encompassing the high-growth deletion in mouse chromosome 10 and identification of the murine Raidd/Cradd gene in the candidate region. Genomics 54: 159-164, 1998. [PubMed: 9806843] [Full Text: https://doi.org/10.1006/geno.1998.5540]
Polla, D. L., Rahikkala, E., Bode, M. K., Maatta, T., Varilo, T., Loman, T., Philips, A. K., Kurki, M., Palotie, A., Korkko, J., Vieira, P., Avela, K., Jacquemin, V., Pirson, I., Abramowicz, M., de Brouwer, A. P. M., Kuismin, O., van Bokhoven, H., Jarvela, I. Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population. Europ. J. Hum. Genet. 27: 1235-1243, 2019. Note: Erratum: Europ. J. Hum. Genet.28: 532 only, 2019. [PubMed: 30914828] [Full Text: https://doi.org/10.1038/s41431-019-0383-8]
Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One 7: e28936, 2012. Note: Electronic Article. [PubMed: 22279524] [Full Text: https://doi.org/10.1371/journal.pone.0028936]
Puffenberger, E. G. Personal Communication. Strasburg, Pa. 2/28/2012.
Tinel, A., Tschopp, J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304: 843-846, 2004. [PubMed: 15073321] [Full Text: https://doi.org/10.1126/science.1095432]