Alternative titles; symbols
HGNC Approved Gene Symbol: MPDZ
Cytogenetic location: 9p23 Genomic coordinates (GRCh38) : 9:13,105,707-13,279,692 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p23 | Hydrocephalus, congenital, 2, with or without brain or eye anomalies | 615219 | Autosomal recessive | 3 |
The PDZ domain (see INADL; 603199) is a protein motif that mediates protein-protein interactions. It has been shown that the PDZ domains of some PDZ-containing proteins interact with the C-terminal tail sequences of specific ion channel subunits and G protein-coupled receptors. To identify proteins that interact with the C-terminal domain of the serotonin 5-HT-2C receptor (312861), Ullmer et al. (1998) screened a human fetal brain cDNA library with the C terminus of the 5-HT-2C receptor using a yeast 2-hybrid system. They isolated a partial cDNA encoding a 454-amino acid polypeptide and used this cDNA to clone a homologous full-length rat brain cDNA. The deduced 2,054-amino acid rat protein, which the authors named Mupp1 for 'multi-PDZ domain protein-1', has 13 PDZ domains, each containing the structural characteristics of a prototypic PDZ motif, but lacks a catalytic domain. The rat Mupp1 protein has high sequence similarity with human INADL. Northern blot analysis detected an 8.5-kb MUPP1 mRNA in several human tissues but not in lung. Some tissues also contained a 4.0- or 5.0-kb transcript, which the authors speculated may be alternative transcripts encoding smaller yet still functional variants of MUPP1.
The full-length human MPDZ coding sequence has been deposited in GenBank (AF093419).
By radiation hybrid and somatic cell hybrid analyses, Ullmer et al. (1998) mapped the MPDZ gene to 9p24-p22.
Gross (2018) mapped the MPDZ gene to chromosome 9p23 based on an alignment of the MPDZ sequence (GenBank BC140793) with the genomic sequence (GRCh38).
In affected members of a consanguineous Saudi family with autosomal recessive congenital hydrocephalus (HYC2; 615219), Al-Dosari et al. (2013) identified a homozygous truncating mutation in the MPDZ gene (Q210X; 603785.0001). The same homozygous mutation was identified in another Saudi patient with the disorder who was stillborn. Haplotype analysis suggested a founder effect, and the mutation age was estimated at 380 years.
In affected members of 3 consanguineous Saudi families with HYC2, Shaheen et al. (2017) identified a homozygous Q210X mutation in the MPDZ gene, consistent with a founder effect in this population. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus. Shaheen et al. (2017) identified biallelic mutations in the MPDZ gene (603785.0002-603785.0005) in 3 additional unrelated patients of various ethnic descent (Palestinian, European, and Kuwaiti) with HYC2. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed.
In affected members of a consanguineous Saudi family with autosomal recessive hydrocephalus (HYC2; 615219), Al-Dosari et al. (2013) identified a homozygous c.628C-T transition in exon 6 of the MPDZ gene, resulting in a gln210-to-ter (Q210X) substitution and the loss of 12 of the 13 PDZ domain, and predicting a loss of function. The mutation, which was found by linkage analysis followed by sequencing of genes in the candidate region, was not present in 200 Saudi exomes or 96 Saudi controls, but was found in heterozygous state in 1 of 6,137 controls in an exome database. The same homozygous mutation was identified in another Saudi patient with the disorder who was stillborn. Haplotype analysis suggested a founder effect, and the mutation age was estimated at 380 years. Many affected individuals died of the disorder in infancy, but 3 were alive, 2 of whom had decreased IQ.
Shaheen et al. (2017) identified a homozygous Q210X mutation in the MPDZ gene in affected members of 3 consanguineous Saudi families (families 4, 5, and 24) with HYC2. The carrier frequency was estimated to be 0.00044. The mutations segregated with the disorder in the families. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus. Functional studies of the variant and studies of patient cells were not performed.
In a 2.5-year-old girl, born of consanguineous Palestinian parents (family 1), with autosomal recessive hydrocephalus-2 (HYC2; 615219), Shaheen et al. (2017) identified a homozygous 1-bp deletion (c.4469delA, NM_001330637.1) in the MPDZ gene, predicted to result in a frameshift and premature termination (Gln1490ArgfsTer19). 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.
In an 8-year-old boy of European descent (family 2) with autosomal recessive hydrocephalus-2 (HYC2; 615219), Shaheen et al. (2017) identified compound heterozygous nonsense mutations in the MPDZ gene: a c.2230C-T transition (c.2230C-T, NM_001330637.1), resulting in an arg744-to-ter (R744X) substitution, and a c.3211C-T transition, resulting in an arg1071-to-ter (R1071X; 603785.0004) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were confirmed to be inherited in trans. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.3211C-T transition (c.3211C-T, NM_001330637.1) in the MPDZ gene, resulting in an arg1071-to-ter (R1071X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive hydrocephalus-2 (HYC2; 615219) by Shaheen et al. (2017), see 603785.0003.
In a 15-month-old boy from Kuwait (family 3) with autosomal recessive hydrocephalus-2 (HYC2; 615219), Shaheen et al. (2017) identified a homozygous c.5278G-A transition (c.5278G-A, NM_001330637.1) in the MPDZ gene, resulting in an ala1760-to-thr (A1760T) substitution. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
Al-Dosari, M. S., Al-Owain, M., Tulbah, M., Kurdi, W., Adly, N., Al-Hemidan, A., Masoodi, T. A., Albash, B., Alkuraya, F. S. Mutation in MPDZ causes severe congenital hydrocephalus. J. Med. Genet. 50: 54-58, 2013. [PubMed: 23240096] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101294]
Gross, M. B. Personal Communication. Baltimore, Md. 9/5/2018.
Shaheen, R., Sebai, M. A., Patel, N., Ewida, N., Kurdi, W., Altweijri, I., Sogaty, S., Almardawi, E., Seidahmed, M. Z., Alnemri, A., Madirevula, S., Ibrahim, N., and 17 others. The genetic landscape of familial congenital hydrocephalus. Ann. Neurol. 81: 890-897, 2017. [PubMed: 28556411] [Full Text: https://doi.org/10.1002/ana.24964]
Ullmer, C., Schmuck, K., Figge, A., Lubbert, H. Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Lett. 424: 63-68, 1998. [PubMed: 9537516] [Full Text: https://doi.org/10.1016/s0014-5793(98)00141-0]