Alternative titles; symbols
HGNC Approved Gene Symbol: PIDD1
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38) : 11:799,184-809,501 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly | 619827 | Autosomal recessive | 3 |
The PIDD1 gene encodes a member of the PIDDosome multiprotein complex that induces apoptosis in response to DNA damage. Together with CRADD (603454), PIDD1 activates caspase-2 (CASP2; 600639). The PIDDosome complex may also play a role in p53 activation upon centrosome accumulation. PIDD1 can also interact with RIP1 (603453) and NEMO (300248) upon DNA damage to promote NFKB activation for cell survival (summary by Sheikh et al., 2021 and Zaki et al., 2021).
The p53 tumor suppressor (TP53; 191170) promotes cell cycle arrest or apoptosis in response to cellular stress, such as DNA damage and oncogenesis. This role of p53 is important for its tumor suppression function and depends, at least in part, on its ability to bind to specific DNA sequences and activate the transcription of target gene. Lin et al. (2000) described a novel gene regulated by p53 that they designated PIDD. The predicted protein is 910 amino acids in humans and 915 amino acids in mouse.
By searching an EST database for sequences containing the death domain of RIP (HRB; 600862), followed by screening, PCR, and 5-prime RACE of leukemia, heart, and brain cDNA libraries, Telliez et al. (2000) cloned LRDD. The deduced 753-amino acid protein has a calculated molecular mass of 83 kD. LRDD contains an N-terminal leucine-rich region (LRR) with 6 repeats of 23 amino acids, followed by a region similar to the spectrin (see SPTA1; 182860)-binding domain of the ankyrins (see ANK3; 600465), and a C-terminal death domain. It also has a possible alternative initiation site downstream of the LRR. Western blot analysis of several human tissues detected LRDD at an apparent molecular mass of 55 kD, with expression higher in kidney and liver, and lower in heart and brain. No LRDD was detected in lung and skeletal muscle. Western blot analysis of COS cells indicated that endogenous monkey Lrdd is proteolytically processed into 2 fragments of 33 and 55 kD, containing the LRR and the death domain, respectively. The 2 fragments appeared to associate with each other.
Lin et al. (2000) found that the mouse Pidd cDNA contains a p53 consensus DNA binding sequence upstream of the Pidd coding region. This sequence element bound to p53 and conferred p53-dependent inducibility on a heterologous reporter gene. In mouse embryonic fibroblasts, Pidd RNA was induced by ionizing radiation in a p53-dependent manner, and the basal level of Pidd RNA was dependent on p53 status. Overexpression of Pidd inhibited cell growth in a p53-like manner by inducing apoptosis. Antisense inhibition of Pidd expression attenuated p53-mediated apoptosis. Lin et al. (2000) suggested that Pidd is an effector of p53-dependent apoptosis.
By coexpression in COS cells, Telliez et al. (2000) determined that LRDD coimmunoprecipitated with FADD (602457) and MADD (603584), but not with TRADD (603500) or RIP. The death domain of LRDD did not appear to self-associate. Overexpression of LRDD did not potentiate or prevent apoptosis induced by TNF (191160) or FAS (TNFRSF6; 134637).
Tinel and Tschopp (2004) showed that activation of caspase-2 (600639) occurs in a complex that contains the death domain-containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD (603454). 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.
Lin et al. (2000) observed human ESTs corresponding to the death domain of mouse Pidd partitioned into a UniGene cluster mapping to chromosome 11p15.5.
In 10 affected members of 2 unrelated consanguineous Pakistani families (ASMR105 and ASMR110), with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Harripaul et al. (2018) identified a homozygous nonsense mutation in the PIDD1 gene (Q863X; 605247.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. The patients were ascertained from a cohort of 192 consanguineous families from Pakistan and Iran with autosomal recessive intellectual disability who underwent whole-exome sequencing.
In affected members of 2 unrelated consanguineous Iranian families (M278 and M8700004) with MRT75, Hu et al. (2019) identified homozygous mutations in the PIDD1 gene (c.2275-1G-A, 605247.0002 and R815W, 605247.0003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The families were part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variants and studies of patient cells were not performed.
Sheikh et al. (2021) performed functional analysis of the 3 PIDD1 mutations identified by Harripaul et al. (2018) and Hu et al. (2019), demonstrating that all disrupted the death domain, abrogated the interaction of PIDD1 with CRADD (603454), and failed to activate caspase-2 (CASP2; 600639), consistent with a loss of function. Sheikh et al. (2021) identified a homozygous nonsense mutation in the PIDD1 gene (R637X; rs578222814) in a 10-year-old Indian girl (Manipal-1) with MRT75. She had an IQ of 75, ADHD, and brain imaging features suggestive of pachygyria. Her 17-year-old brother had normal development, and IQ of 104, no behavioral problems, and normal brain imaging. It was not clear in the paper whether or not the brother carried the mutation. Functional studies of the R637X variant were not performed.
In 11 patients from 6 unrelated consanguineous families with MRT75, Zaki et al. (2021) identified 5 different homozygous mutations in the PIDD1 gene (see, e.g., 605247.0004-605247.0006). There were 4 frameshift or nonsense mutations, predicted to result in a loss of function, and 1 missense variant (R862W; 605247.0004) that occurred in the death domain and was predicted to destabilize the interaction of PIDD1 with CRADD. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None were present in the homozygous state in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed.
Sheikh et al. (2021) found that Pidd1-null mice were similar to wildtype at 3 and 12 months of age. Mutant mice did not show significant changes from wildtype, although there was some evidence for decreased anxiety-like behavior.
In 10 affected members of 2 unrelated consanguineous Pakistani families (ASMR105 and ASMR110), with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Harripaul et al. (2018) identified a homozygous c.2587C-T transition (c.2587C-T, NM_145886.3) in the PIDD1 gene, resulting in a gln863-to-ter (Q863X) substitution that disrupts the death domain (DD). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a follow-up study, Sheikh et al. (2021) noted that the Q863X mutation occurs in the last exon, suggesting that it may escape nonsense-mediated mRNA decay. If a protein were produced, it would interrupt the DD domain. The Q863X mutation was found once in the heterozygous state in the gnomAD database (1 of 246,378 chromosomes, frequency of 4 x 10(-6)). Transfection of the mutation into HEK293 cells indicated that the mutation interfered with PIDD1 protein stability. In vitro immunoprecipitation and functional studies in transfected HEK293 cells showed that the mutation ablated the interaction of PIDD1 with CRADD (603454) and failed to activate caspase-2 (CASP2; 600639), consistent with a loss of function.
In 2 sibs, born of consanguineous parents (family M278), with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Hu et al. (2019) identified a homozygous G-to-A transition (c.2275-1G-A, NM_145886) in the PIDD1 gene, predicted to result in a splicing abnormality and a loss-of-function effect. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variants and studies of patient cells were not performed.
In a follow-up study, Sheikh et al. (2021) stated that this splice site mutation occurs just ahead of exon 14 and is not present in the gnomAD database. Using an exon-trap construct, Sheikh et al. (2021) determined that the c.2275-1G-A mutation causes the skipping of exon 15 with direct splicing from exon 14 to the terminal exon 16, causing a frameshift and premature termination (Arg759GlyfsTer1). The would lead to exclusion of the entire DD domain. Transfection of the mutation into HEK293 cells suggested impaired processing of the PIDD1-CC isoform. In vitro immunoprecipitation studies and functional studies showed that the mutation ablated the interaction of PIDD1 with CRADD (603454) and failed to activate caspase-2 (CASP2; 600639), consistent with a loss of function.
In 3 sibs, born of consanguineous Middle Eastern parents (family M8700004), with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Hu et al. (2019) identified a homozygous c.2443C-T transition (c.2443C-T, NM_145886) in the PIDD1 gene, resulting in an arg815-to-trp (R815W) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variants and studies of patient cells were not performed.
In a follow-up study, Sheikh et al. (2021) noted that the R815W mutation, which localizes to the death domain (DD), is present twice in the heterozygous state in the gnomAD database (2 of 266,508 alleles, frequency of 7.5 x 10(-6)). In vitro immunoprecipitation and functional studies in transfected HEK293 cells showed that the mutation ablated the interaction of PIDD1 with CRADD (603454) and failed to activate caspase-2 (CASP2; 600639), consistent with a loss of function.
In 3 patients from 2 unrelated consanguineous Egyptian families (families 1 and 2) with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Zaki et al. (2021) identified a homozygous c.2584C-T transition in the PIDD1 gene, resulting in an arg862-to-trp (R862W) substitution at a highly conserved residue in the death domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to destabilize the interaction of PIDD1 with CRADD (603454). The patients had mild to moderate intellectual disability (IQ range 42 to 56), behavioral abnormalities, including ADHD, autism, and psychosis, anterior predominant pachygyria on brain imaging, and dysmorphic facial features.
In 3 sibs, born of consanguineous Pakistani parents (family 4) with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Zaki et al. (2021) identified a homozygous 5-bp deletion (c.2116_2120del) in the PIDD1 gene, predicted to result in a frameshift and premature termination (Val706HisfsTer30). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to undergo nonsense-mediated mRNA decay and result in a loss of function. The patients had moderate intellectual disability with poor speech and aggressive and self-injurious behavior. Two patients who were imaged showed frontal or diffuse pachygyria.
In 2 brothers, born of consanguineous Colombian parents (family 6) with autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly (MRT75; 619827), Zaki et al. (2021) identified a homozygous 2-bp deletion (c.1804_1805del) in the PIDD1 gene, predicted to result in a frameshift and premature termination (Gly602fsTer26). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in nonsense-mediated mRNA decay and a loss of function. The patients had mild intellectual disability (IQ of 68 and 60), poor speech, ADHD, and anterior-predominant pachygyria.
Harripaul, R., Vasli, N., Mikhailov, A., Rafiq, M. A., Mittal, K., Windpassinger, C., Sheikh, T. I., Noor, A., Mahmood, H., Downey, S., Johnson, M., Vleuten, K., and 20 others. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Molec. Psychiat. 23: 973-984, 2018. [PubMed: 28397838] [Full Text: https://doi.org/10.1038/mp.2017.60]
Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Herwig, R., Hosseini, M., Oppitz, C., Abedini, S. S., Suckow, V., Larti, F., Beheshtian, M., Lipkowitz, B. Genetics of intellectual disability in consanguineous families. Molec. Psychiat. 24: 1027-1039, 2019. [PubMed: 29302074] [Full Text: https://doi.org/10.1038/s41380-017-0012-2]
Lin, Y., Ma, W., Benchimol, S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nature Genet. 26: 122-127, 2000. [PubMed: 10973264] [Full Text: https://doi.org/10.1038/79102]
Sheikh, T. I., Vasli, N., Pastore, S., Kharizi, K., Harripaul, R., Fattahi, Z., Pande, S., Naeem, F., Hussain, A., Mir, A., Islam, O., Girisha, K. M., and 10 others. Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability. Transl. Psychiat. 11: 1, 2021. [PubMed: 33414379] [Full Text: https://doi.org/10.1038/s41398-020-01158-w]
Telliez, J.-B., Bean, K. M., Lin, L.-L. LRDD, a novel leucine rich repeat and death domain containing protein. Biochim. Biophys. Acta 1478: 280-288, 2000. [PubMed: 10825539] [Full Text: https://doi.org/10.1016/s0167-4838(00)00029-7]
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]
Zaki, M. S., Accogli, A., Mirzaa, G., Rahman, F., Mohammed, H., Porras-Hurtado, G. L., Efthymiou, S., Maqbool, S., Shukla, A., Vincent, J. B., Hussain, A., Mir, A., Beetz, C., Leubauer, A., Houlden, H., Gleeson, J. G., Maroofian, R. Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features. Europ. J. Hum. Genet. 29: 1226-1234, 2021. [PubMed: 34163010] [Full Text: https://doi.org/10.1038/s41431-021-00910-0]