Alternative titles; symbols
HGNC Approved Gene Symbol: MADD
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,269,188-47,330,031 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | DEEAH syndrome | 619004 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia | 619005 | Autosomal recessive | 3 |
The MADD gene encodes a MAPK-activating protein that belongs to the DENN protein family, which regulates the Rab family is small GTPases. MADD acts as a guanine nucleotide exchange factor (GEF) for Rab3 (see 602536), which itself is present on synaptic vesicles and regulates neurotransmitter release. MADD also interacts with TNFR1 (191190), which stimulates intracellular signaling pathways and activation of transcription factors under stress conditions. The MADD gene undergoes extensive splicing and generates at least 7 different isoforms with variable tissue expression (summary by Schneeberger et al., 2020).
Chow and Lee (1996) reported the cDNA sequence of DENN, a novel human gene that is differentially expressed in normal and neoplastic cells (hence, the symbol DENN). Northern blot analysis revealed differential levels of expression of a 6.5-kb DENN transcript in malignant cell lines compared to normal human tissues, where expression was highest in fetal brain and kidney and in adult testis, ovary, brain, and heart. In fetal liver and in several human cancer cell lines, the authors identified cDNAs representing alternative transcripts of DENN that harbor a deletion of 129 bp encoding 43 amino acids. Present within the serine- and leucine-rich DENN gene product is an arginyl-glycyl-aspartic acid (RGD) cellular adhesion motif and a leucine zipper-like motif.
Using the yeast interaction trap system to identify proteins that interact with the death domain of the type-1 tumor necrosis factor receptor (TNFR1; 191190), Schievella et al. (1997) isolated cDNAs encoding 'MAP kinase-activating death domain' (MADD) protein. Immunoblotting of immunoprecipitated proteins from various human cell lines detected an approximately 200-kD MADD protein. The deduced 1,588-amino acid MADD protein contains a C-terminal death domain.
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned KIAA0358. The deduced protein contains 1,581 amino acids and is nearly identical to DENN.
Chow et al. (1998) stated that the DENN and MADD cDNAs and proteins are virtually identical. From genomic studies, they traced the alternative splicing of a 129-bp fragment to an alternative 5-prime donor site involving exon 7. The deduced longer DENN isoform has 1,587 amino acids. Western blot analysis of human MOLT-4 T-lymphoblastic leukemic cell proteins detected a doublet consisting of 138- and 142-kD polypeptides. The authors found the DENN protein concentrated predominantly in the cytosolic compartment of MOLT-4 cells but was restricted to the nuclear compartment of PLC/PRF/5 hepatoma cells.
Efimova et al. (2004) identified 7 putative splice variants of MADD: IG20 full-length (IG20FL), IG20, KIAA0358, MADD (also referred to as DENN), IG20 short variant-2 (IG20SV2), DENNSV (also referred to as IG20SV3), and IG20SV4. These variants arise from alternative splicing of exons 13L, 16, 21, 26, and 34. IG20FL, the longest variant, is encoded by all 36 exons of the MADD gene. RT-PCR detected variable expression of IG20, MADD, IG20SV, and DENNSV in all human tissues examined. Expression of KIAA0358, IG20FL, and IG20SV4 was not observed.
Schievella et al. (1997) found that the MADD protein associated with TNFR1 through a death domain-death domain interaction. Overexpression of MADD activated the mitogen-activated protein (MAP) kinase ERK2 (176948), and expression of the MADD death domain stimulated both the ERK2 and JNK1 (601158) MAP kinases and induced the phosphorylation of cytosolic phospholipase A2 (600522). The authors suggested that MADD links TNFR1 with MAP kinase activation and arachidonic acid release.
Al-Zoubi et al. (2001) showed that HeLa cells permanently transfected with IG20 or DENNSV were more susceptible or resistant to TNF-alpha (TNFA; 191160)-induced apoptosis, respectively. All MADD variants tested could interact with TNFR1 and activate ERK and NF-kappa-B (see 164011). However, relative to control cells, only those expressing IG20 showed enhanced TNF-alpha-induced activation of caspase-8 (CASP8; 601763) and CASP3 (600636). Cowpox virus CrmA, an inhibitor of caspase-induced apoptosis, inhibited apoptosis when transfected in IG20-expressing HeLa cells.
Using specific small hairpin RNAs targeted to splice variants of the MADD gene, Mulherkar et al. (2006) found that knockdown of the MADD variant resulted in spontaneous apoptosis in HeLa cells and in a human ovarian carcinoma cell line, and they demonstrated that the MADD variant alone was necessary and sufficient for cancer cell survival. Mulherkar et al. (2006) hypothesized that since the MADD variant can bind to death receptors, it may prevent apoptotic signaling by interfering with death receptor oligomerization.
Efimova et al. (2004) found that overexpression of DENNSV enhanced cell replication and resistance to treatment with proapoptotic stimuli. In contrast, IG20 expression suppressed cell replication and increased susceptibility to proapoptotic stimuli. Moreover, cells that were resistant or susceptible to TNF-alpha-induced apoptosis exclusively expressed endogenous DENNSV and IG20, respectively. Transfection of IG20 in a DENNSV-expressing cell line overrode endogenous DENNSV function and increased susceptibility to apoptotic stimuli. Dominant-negative I-kappa-B (see NFKBIA; 164008) reversed the effects of DENNSV, but not IG20, indicating that DENNSV functions through NF-kappa-B activation.
Using knockdown analysis in mouse melanocytes, Figueiredo et al. (2008) identified Rab3gep as a nonredundant GEF specific for activation of Rab27a (603868). Knockdown of Rab3gep resulted in melanosome aggregation by reducing levels of activated Rab27a, as Rab27a was predominantly in its GDP-bound, nonactive form in Rab3gep-depleted cells. In vitro analysis with purified recombinant proteins confirmed that Rab3gep was a GEF specific for Rab27a.
Chow et al. (1998) determined that the MADD gene spans at least 28 kb and contains 15 exons, ranging in size from 73 to 1,230 bp.
Efimova et al. (2004) determined that the MADD gene contains 36 exons.
By radiation hybrid analysis, Nagase et al. (1997) mapped the MADD gene to chromosome 11. Using FISH, Chow et al. (1998) mapped the MADD gene to chromosome 11p11.2.
Neurodevelopmental Disorder with Dysmorphic Facies, Impaired Speech, and Hypotonia
In a 6-year-old girl (17DG0770) with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005), Anazi et al. (2017) identified compound heterozygous mutations in the MADD gene (R198H, 603584.0001 and R327X, 603584.0002). The mutations, which were found by exome sequencing of 68 families with intellectual disability, were confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the nonsense mutation was predicted to disrupt the DENN domain including the GTPase binding site.
In 2 adult sisters, born of unrelated Iranian parents (family M135), with NEDDISH, Hu et al. (2019) identified compound heterozygous mutations in the MADD gene (603584.0003 and 603584.0004). The mutations were 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 9 patients (patients 15-23) from 6 families (families 12-17) with NEDDISH, Schneeberger et al. (2020) identified homozygous or compound heterozygous mutations in the MADD gene (see, e.g., 603584.0004 and 603584.0009). The families were of various ethnic descents, including Persian and Caucasian, and the patients were ascertained through international collaboration. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Most were absent from the gnomAD database, but 1 was present at a low frequency. Missense, nonsense, and frameshift mutations were identified. In vitro functional expression studies of fibroblasts derived from 1 patient (patient 18) showed disruption of several MADD functions compared to controls (see 603584.0009), consistent with a loss-of-function or hypomorphic effect.
Developmental Delay with Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities
In 14 patients from 11 families (families 1 to 11) with developmental delay with endocrine, exocrine, autonomic, and hematologic abnormalities (DEEAH syndrome; 619004), Schneeberger et al. (2020) identified homozygous or compound heterozygous mutations in the MADD gene (see, e.g., 603584.0005-603584.0008). The families were of various ethnic descent, including Arab, Pakistani, South American, and Caucasian, and the patients were ascertained through international collaboration. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Most were absent from the gnomAD database, but a few were present at a low frequency. Most patients carried a nonsense, frameshift, or splice site mutation on at least 1 allele, but 2 patients had homozygous missense mutations. In vitro functional expression studies of some of the mutations showed impaired TNFA (191160)-induced activation of the MAPK signaling pathway compared to controls. Patient cells showed enhanced susceptibility to TNFA-dependent apoptosis as well as other cellular stressors that resulted in activation of the intrinsic apoptosis pathway. Finally, patient cells showed decreased internalization of epidermal growth factor (EGF; 131530) compared to controls, which suggested a defect in the activation of small GTPase proteins and a disruption of vesicle trafficking, such as exocytosis. Overall, these data were consistent with a loss-of-function or hypomorphic effect of the mutations on MADD function. Schneeberger et al. (2020) noted that while there were not apparent genotype/phenotype correlations, mutation-specific disruption of the various MADD functions might underlie the clinical variability observed in the patients.
Schneeberger et al. (2020) noted that Anazi et al. (2017) had identified a homozygous missense mutation (variously reported as V977G, L977R, and L1040R) in the MADD gene in 14-month-old girl (17DG0771), born of consanguineous parents, with a similar disorder resulting in early death. Anazi et al. (2017) did not perform functional studies of the variant.
In a 6-year-old girl (17DG0770) with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005), Anazi et al. (2017) identified compound heterozygous mutations in the MADD gene: a c.593G-A transition (c.593G-A, NM_001135943.1) resulting in an arg198-to-his (R198H) substitution, and a c.979C-T transition, resulting in an arg327-to-ter (R327X; 603584.0002) substitution. The mutations, which were found by exome sequencing of 68 families with intellectual disability, were confirmed by Sanger sequencing. Both mutations occurred in the DENN domain. Functional studies of the variants and studies of patient cells were not performed, but the nonsense mutation was predicted to disrupt the DENN domain including the GTPase binding site.
For discussion of the c.979C-T transition (c.979C-T, NM_001135943.1) in the MADD gene, resulting in an arg327-to-ter (R327X) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005) by Anazi et al. (2017), see 603584.0001.
In 2 adult sisters, born of unrelated Iranian parents (family M135), with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005), Hu et al. (2019) identified compound heterozygous mutations in the MADD gene: a 1-bp deletion (c.3559del, NM_003682), resulting in a frameshift and premature termination (Met1187Ter) and a c.1061C-T transition, resulting in a pro354-to-leu (P354L; 603584.0004) substitution. The mutations were 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.
For discussion of the c.1061C-T transition (c.1061C-T, NM_003682) in the MADD gene, resulting in a pro354-to-leu (P354L) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005) by Hu et al. (2019), see 603584.0003.
For discussion of the P354L substitution (c.1061C-T, NM_003682.3) in the MADD gene that was found in compound heterozygous state in 2 sibs (patients 18 and 19) with NEDDISH by Schneeberger et al. (2020), see 603584.0009. The P354L missense variant was present at a low frequency (0.002) in the gnomAD database. Analysis of patient cells showed about a 50% decrease in mRNA levels, but almost complete absence of the MADD protein (less than 4%) suggesting that the P354L protein is unstable.
In 2 sibs (patients 1 and 2, family 1) with DEEAH syndrome (DEEAH; 619004), Schneeberger et al. (2020) identified compound heterozygous mutations in the MADD gene: a c.914G-T transversion (c.914G-T, NM_003682.3), resulting in a gly305-to-val (G305V) substitution, and an intragenic deletion (c.1862+1_1863-1_3759+1_3760-1), resulting in the deletion of exons 11 to 24. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in public databases, including dbSNP (build 138) and gnomAD. Analysis of patient fibroblasts indicated that the deletion resulted in the production of several abnormal transcripts that underwent nonsense-mediated mRNA, consistent with a loss-of-function effect of this mutation. Patient cells showed almost complete absence of the MADD protein (less than 4% of controls), suggesting that the mutant missense protein is unstable.
For discussion of the intragenic deletion in the MADD gene (c.1862+1_1863-1_3759+1_3760-1, NM_003682.3), resulting in the deletion of exons 11 to 24, that was found in compound heterozygous state in 2 sibs with DEEAH syndrome (DEEAH; 619004) by Schneeberger et al. (2020), see 603584.0005.
In 2 sibs (patients 3 and 4, family 2) with DEEAH syndrome (DEEAH; 619004), Schneeberger et al. (2020) identified a homozygous G-to-A transition in intron 4 of the MADD gene (c.963+1G-A, NM_003682.3), resulting in a splicing defect. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient cells showed that the mutation resulted in the production of several abnormal transcripts that were predicted to disrupt or terminate the protein. Patient cells showed about a 50% decrease in mRNA and almost complete absence of the MADD protein (less than 4% of controls).
In a patient (patient 11) with DEEAH syndrome (DEEAH; 619004), Schneeberger et al. (2020) identified a homozygous c.770C-T transition (NM_003682.3) in intron 4 of the MADD gene, resulting in a ser257-to-phe (S257F) substitution at a conserved residue in the DENN domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient cells showed normal mRNA levels, but almost complete absence MADD protein (less than 4% of control levels), suggesting that the mutant protein is unstable.
In 2 sibs (patients 18 and 19) with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH; 619005), Schneeberger et al. (2020) identified compound heterozygous mutations in the MADD gene: a 2-bp deletion (c.3637_3638delAG, NM_003682.3), resulting in a frameshift and premature termination (Ser1213Ter), and P354L (603584.0004). The mutation, which was found by sequence analysis of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. The frameshift mutation was not present in the gnomAD database, whereas the missense variant was present at a low frequency (0.002). Analysis of patient cells showed about a 50% decrease in mRNA levels, but almost complete absence of the MADD protein (less than 4% of control levels), suggesting that the P354L protein is unstable. In vitro functional expression studies of fibroblasts derived from patient 18 showed impaired TNFA (191160)-induced activation of the MAPK signaling pathway compared to controls. Patient cells showed enhanced susceptibility to TNFA-dependent apoptosis as well as other cellular stressors that resulted in activation of the intrinsic apoptosis pathway. Finally, patient cells showed decreased internalization of epidermal growth factor (EGF; 131530) compared to controls, which suggested a defect in the activation of small GTPase proteins and a disruption of vesicle trafficking, such as exocytosis. Overall, these data were consistent with a loss-of-function or hypomorphic effect.
Al-Zoubi, A. M., Efimova, E. V., Kaithamana, S., Martinez, O., El-Azami El-Idrissi, M., Dogan, R. E., Prabhakar, B. S. Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor-necrosis factor alpha-induced apoptosis and activation of caspase-8 and -3. J. Biol. Chem. 276: 47202-47211, 2001. [PubMed: 11577081] [Full Text: https://doi.org/10.1074/jbc.M104835200]
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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]
Mulherkar, N., Ramaswamy, M., Mordi, D. C., Prabhakar, B. S. MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival. Oncogene 25: 6252-6261, 2006. [PubMed: 16682944] [Full Text: https://doi.org/10.1038/sj.onc.1209650]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Schievella, A. R., Chen, J. H., Graham, J. R., Lin, L.-L. MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. J. Biol. Chem. 272: 12069-12075, 1997. [PubMed: 9115275] [Full Text: https://doi.org/10.1074/jbc.272.18.12069]
Schneeberger, P. E., Kortum, F., Korenke, G. C., Alawi, M., Santer, R., Woidy, M., Buhas, D., Fox, S., Juusola, J., Alfadhel, M., Webb, B. D., Coci, E. G., and 34 others. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder. Brain 143: 2437-2453, 2020. [PubMed: 32761064] [Full Text: https://doi.org/10.1093/brain/awaa204]