Alternative titles; symbols
HGNC Approved Gene Symbol: MCM3AP
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38) : 21:46,235,133-46,286,265 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development | 618124 | Autosomal recessive | 3 |
The MCM3AP gene encodes a protein that binds to and acetylates MCM3, thereby inhibiting cell cycle progression (summary by Schuurs-Hoeijmakers et al., 2013). The MCM3AP gene also encodes an alternatively spliced variant named 'germinal center-associated nuclear protein' (GANP), which contains a Sac3 domain that is responsible for exporting mRNAs to the cytoplasm through the nuclear pores (summary by Karakaya et al., 2017).
The MCM3 (602693) protein is essential for the initiation of DNA replication and also participates in controls that ensure that DNA replication initiates only once per cell cycle. Using a yeast 2-hybrid assay with MCM3 as bait, Takei and Tsujimoto (1998) isolated a liver cDNA encoding a protein they designated MAP80 (MCM3-associated protein-80). The predicted 721-amino acid MAP80 has an estimated pI of 5.1. Antibodies against MAP80 detected an 80-kD protein on Western blots of HeLa cell extracts.
By screening human brain cDNAs for those encoding proteins larger than 50 kD, Nagase et al. (1998) identified KIAA0572, a MAP80 cDNA. The in vitro transcribed/translated product of the cDNA had a molecular mass of greater than 100 kD by SDS-PAGE. RT-PCR revealed that MAP80 is expressed ubiquitously.
By screening a heart cDNA library with mouse Ganp, Abe et al. (2000) isolated a cDNA encoding GANP. The deduced 1,980-amino acid protein is nearly identical to the partial sequence for KIAA0572 (Nagase et al., 1998), 78% similar to mouse Ganp, and identical to MAP80 (Takei and Tsujimoto, 1998) over its C-terminal 721 amino acids. Structure analysis predicted the presence of a nuclear localization signal, a coiled-coil structure, and 4 LXXLL motifs typical of nuclear transcription activators. Genomic sequence and Southern blot analysis determined that MAP80 and GANP originate from the same genetic element by alternative splicing. Northern blot analysis detected ubiquitous expression of a 7.0-kb transcript. RT-PCR analysis was required to detect MAP80 expression. In situ hybridization analysis demonstrated that GANP is upregulated in the germinal center of the tonsil. Immunohistochemical analysis showed that the localization coincides with the region containing CD38 (107270)-positive/IgD (see 147170)-negative/CD23 (151445)-negative memory B cells.
Ylikallio et al. (2017) found expression of the MCM3AP gene in human induced pluripotent stem cells (iPSCs) that were differentiated towards a neuronal lineage, confirming that it is expressed in neuronal cells. Immunostaining detected punctate localization of MCM3AP at the nuclear envelope, consistent with its described role in nuclear pore complexes.
Takei and Tsujimoto (1998) found that MAP80 coimmunoprecipitated with MCM3 in HeLa cell extracts. In the presence of a small amount of cytosol, recombinant MAP80 facilitated the nuclear import of a chimeric GFP-MCM3 protein. Using a yeast 2-hybrid assay, Takei and Tsujimoto (1998) showed that mutagenesis of the MCM3 nuclear localization signal weakened the interaction between MCM3 and MAP80. They concluded that MAP80 is involved in the nuclear localization of MCM3.
Using yeast 2-hybrid and protein pull-down assays, Kono et al. (2002) found that mouse G5pr (PPP2R3C; 615902) interacted with Ganp DNA primase and with 2 types of catalytic protein phosphatases, Pp2ca (PPP2CA; 176915) and Pp5 (PPP5C; 600658). G5pr did not interact with Pp2ca and Pp5 simultaneously. In vitro-phosphorylated Mcm3 was dephosphorylated by the G5pr complex in the absence of okadaic acid, an inhibitor of both Pp2ca and Pp5, and dephosphorylation was enhanced by arachidonic acid, a Pp5 activator.
By analysis of a radiation hybrid panel, Nagase et al. (1998) mapped the MCM3AP gene to chromosome 21. Using FISH, Abe et al. (2000) mapped the MCM3AP gene to 21q22.3.
In a Dutch brother and sister, born of unrelated parents, with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Schuurs-Hoeijmakers et al. (2013) identified a homozygous missense mutation in the MCM3AP gene (E915K; 603294.0001) affecting a highly conserved residue in the Sac3 domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. DNA from the parents was not available for segregation analysis. Schuurs-Hoeijmakers et al. (2013) noted that the MCM3AP gene is expressed in the brain or in neuronal tissue.
In 9 patients from 5 unrelated families with PNRIID, Ylikallio et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0002-603294.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients in 4 families were compound heterozygous for a missense mutation affecting a conserved residue and a frameshift, nonsense, or splice site mutation, predicted to result in a loss of function or to be subjected to nonsense-mediated mRNA decay. Fibroblasts derived from 1 patient (family F) showed significantly decreased levels of MCM3AP mRNA and protein levels of 20% compared to controls, whereas fibroblasts from the affected individual in family A showed a milder decrease in protein levels at about 85% of controls. Patient cells did not show a deficit in DNA repair. Ylikallio et al. (2017) postulated that the mutations resulted in a partial or complete loss of protein function, possibly leading to abnormal nuclear retention of mRNAs that are crucial for neuronal function.
In 4 patients from 3 unrelated families with PNRIID, Karakaya et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0006 and 603294.0007). The mutations were found by targeted sequencing of a gene panel and confirmed by Sanger sequencing. Segregation studies confirmed recessive inheritance in 2 of the families. Functional studies of the variants and studies of patient cells were not performed, but 2 families carried homozygous missense mutations in the Sac3 domain, and the third family was compound heterozygous for a nonsense and a frameshift mutation. Two families were consanguineous and of Kurdish and Iranian descent, respectively.
In 3 sibs of Lebanese ethnicity with PNRIID, Kennerson et al. (2018) identified a homozygous missense mutation in the Sac3 domain of the MCM3AP gene (L870S; 603294.0008). The mutation, which was found by whole-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 a girl of Dutch and Thai ancestry and 2 Estonian sibs with PNRIID, Woldegebriel et al. (2020) identified compound heterozygous mutations in the MCM3AP gene (603294.0009-603294.0012). All 4 mutations were located outside of the Sac3 domain of the GANP protein. Woldegebriel et al. (2020) studied GANP expression in skin fibroblasts from 9 patients with PNRIID, including their 3 patients. Two of the fibroblast lines were from patients who were heterozygous or homozygous for the S951P mutation (603294.0007) located in the Sac3 domain and the other fibroblast lines were from patients with compound heterozygous mutations outside the Sac3 domain. In fibroblasts from patients with mutations outside the Sac3 domain there was decreased GANP at the level of the nuclear envelope, and in fibroblasts from 2 patients with variants in the Sac3 domain, GANP had normal expression and localization. The patients with decreased GANP appeared to have a more severe phenotype compared to patients with mutations in the Sac3 domain.
In a Dutch brother and sister, born of unrelated parents, with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Schuurs-Hoeijmakers et al. (2013) identified a homozygous c.2743G-A transition in the MCM3AP gene, resulting in a glu915-to-lys (E915K) substitution at a highly conserved residue. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. DNA from the parents was not available for segregation analysis. Schuurs-Hoeijmakers et al. (2013) noted that the MCM3AP gene is expressed in the brain or in neuronal tissue. No functional studies on the variant were performed. The patients also had progressive polyneuropathy, cerebellar ataxia, ptosis, saccadic eye movements, hypotonia, and facial dysmorphism. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing.
In 3 Finnish sibs (family F) with autosomal recessive peripheral neuropathy with or without impaired intellectual development (PNRIID; 618124), Ylikallio et al. (2017) identified compound heterozygous mutations in the MCM3AP gene: a c.3814G-A transition (c.3814G-A, NM_003906.4) in exon 17, resulting in a val1272-to-met (V1272M) substitution at a conserved residue, and a 1-bp deletion in exon 1 (c.443delC; 603294.0003), resulting in a frameshift and premature termination (Pro148LeufsTer48). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The frameshift variant was not found in the ExAC database, whereas V1272M was found at low frequency in the European and Finnish populations (0.0002 and 0.0057, respectively). Patient cells showed decreased levels of the MCM3AP protein, at 20% of control values. Additional functional studies were not performed.
For discussion of the 1-bp deletion (c.443delC, NM_003906.4) in the MCM3AP gene, resulting in a frameshift and premature termination, that was found in compound heterozygous state in a family with autosomal recessive peripheral neuropathy, with or without impaired intellectual development (PNRIID; 618124) by Ylikallio et al. (2017), see 603294.0002.
In an 8-year-old Australian girl (family A) with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Ylikallio et al. (2017) identified compound heterozygous mutations in the MCM3AP gene: a c.2600C-A transversion (c.2600C-A, NM_003906.4) in exon 9, resulting in an ala867-to-asp (A867D) substitution at a conserved residue, and a c.2667C-A transversion in exon 10, resulting in a tyr889-to-ter (Y889X; 603294.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the ExAC database. The A867D variant was inherited from the unaffected mother and the Y889X variant occurred de novo. Both mutations occurred in the Sac3 domain, but functional studies of the variants were not performed. Patient cells showed only a mild decrease in MCM3AP protein levels, at about 85% of control values.
For discussion of the c.2667C-A transversion (c.2667C-A, NM_003906.4) in exon 10 of the MCM3AP gene, resulting in a tyr889-to-ter (Y889X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124) by Ylikallio et al. (2017), see 603294.0004.
In an 8-year-old girl, born of consanguineous Kurdish parents (family A), with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Karakaya et al. (2017) identified a homozygous c.2633G-A transition (c.2633G-A, NM_003906.3) in the MCM3AP gene, resulting in an arg878-to-his (R878H) substitution at a conserved residue in the Sac3 domain. The mutation was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing. The variant was found in heterozygous state in 3 of 243,616 alleles in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 2 sisters, born of consanguineous Iranian parents (family B), with autosomal recessive peripheral neuropathy without impaired intellectual development (PNRIID; 618124), Karakaya et al. (2017) identified a homozygous c.2851T-C transition (c.2851T-C, NM_003906.3) in the MCM3AP gene, resulting in a ser951-to-pro (S951P) substitution at a conserved residues in the Sac3 domain. The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the gnomAD database or in 600 in-house controls. Functional studies of the variant and studies of patient cells were not performed.
In 3 sibs of Lebanese ethnicity with autosomal recessive peripheral neuropathy without impaired intellectual development (PNRIID; 618124), Kennerson et al. (2018) identified a homozygous c.2609T-C transition (c.2609T-C, NM_003906.3) in exon 9 of the MCM3AP gene, resulting in a leu870-to-ser (L870S) substitution at a highly conserved residue in the Sac3 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP (build 150), gnomAD, or 1000 Genomes Project databases, or in 100 in-house controls. Functional studies of the variant and studies of patient cells were not performed.
In a patient (NL2) of Dutch and Thai ancestry with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Woldegebriel et al. (2020) identified compound heterozygous mutations in the MCM3AP gene: a paternally inherited 2-bp deletion (c.3476_3477del), predicted to result in a frameshift and premature termination (Gln1159ArgfsTer8), and a maternally inherited c.4290+3G-T transversion (603294.0010), predicted to result in abnormal splicing. The mutations, which were found by whole-exome sequencing, were not present in the ExAC database. MCM3AP mRNA expression was reduced in patient fibroblasts compared to controls, and GANP protein levels were reduced at the level of the nuclear envelope in patient fibroblasts compared to controls.
For discussion of the c.4290+3G-T transversion in the MCM3A gene that was identified in compound heterozygous state in a patient with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124) by Woldegebriel et al. (2020), see 603294.0009.
In 2 Estonian sibs (EST1 and EST2) with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124), Woldegebriel et al. (2020) identified compound heterozygous mutations in the MCM3AP gene: a c.3814G-A transition, resulting in a val1272-to-met (V1272M) substitution, and a 1-bp deletion (c.5423delG; 603294.0012), predicted to result in a frameshift and premature termination (Gly1808AspfsTer5). The mutations, which were identified by whole-genome sequencing, were found in the heterozygous state in the parents. Both mutations had an allele frequency of about 0.0025 in the Finnish population in the gnomAD database. MCM3AP mRNA expression was reduced in patient fibroblasts compared to controls, and GANP protein levels were reduced at the level of the nuclear envelope in patient fibroblasts compared to controls.
For discussion of the 1-bp deletion (c.5423delG) in the MCM3AP gene, predicted to result in a frameshift and premature termination (Gly1808AspfsTer5), that was identified in compound heterozygous state in sibs with autosomal recessive peripheral neuropathy with impaired intellectual development (PNRIID; 618124) by Woldegebriel et al. (2020), see 603294.0011.
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