Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 602296

Alternative titles; symbols

MU-ARP2

HGNC Approved Gene Symbol: AP4M1

Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38) : 7:100,100,794-100,109,039 (from NCBI)

Gene-Phenotype Relationships

Location Phenotype Phenotype MIM number Inheritance Phenotype mapping key
7q22.1 Spastic paraplegia 50, autosomal recessive 612936 Autosomal recessive 3

TEXT

Description

The AP4M1 gene encodes a subunit of the heterotetrameric adaptor protein (AP) complex, a component of intracellular transport of proteins that is thought to have a unique role in neurons. AP4 is composed of 2 large chains, beta-4 (AP4B1; 607245) and epsilon-4 (AP4E1; 607244), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1; 607243) (summary by Tuysuz et al., 2014).

Cloning and Expression

Using a combination of sequence database searching and PCR from a human brainstem cDNA library, Wang and Kilimann (1997) isolated a cDNA encoding mu-adaptin-related protein-2 (mu-ARP2). The predicted 434-amino acid mu-ARP2 sequence is 31% identical to those of mu-adaptins, the medium chains of the clathrin coat adaptor complexes. Wang and Kilimann (1997) showed by Northern blot analysis that the mu-ARP2 gene was expressed in all tissues examined, with the highest level in testis. They speculated that mu-ARP2 is a subunit of a novel type of clathrin- or non-clathrin-associated protein coat involved in membrane trafficking.

By immunoprecipitation of HeLa cell lysates, Dell'Angelica et al. (1999) identified AP4M1 as a 50-kD protein within the 280-kD AP4 complex. Immunolocalization of the AP4B1 subunit in HeLa cells revealed that the AP4 complex associates with the trans-Golgi network or an adjacent structure. The association was sensitive to brefeldin-A treatment, indicating that the membrane localization of AP4 is dependent upon the small GTP-binding protein ARF1 (103180).

Hirst et al. (1999) cloned AP4M1 from a brain cDNA library. The predicted 453-amino acid AP4M1 protein contains the YELLDE motif common to other AP mu subunits. Coimmunoprecipitation of pig brain cytosol confirmed the association of AP4M1 with other AP4 proteins. Direct interaction between AP4B1 and AP4M1 was demonstrated in a yeast 2-hybrid assay.

Mapping

Gross (2023) mapped the AP4M1 gene to chromosome 7q22.1 based on an alignment of the AP4M1 sequence (GenBank AF020796) with the genomic sequence (GRCh38).

Gene Function

Hirst et al. (1999) noted that the mu subunits of other AP complexes interact with a tyrosine-based sorting signal, YXXO (where X is any amino acid and O is a bulky hydrophobic residue). Using a yeast 2-hybrid assay, they found specific interaction between AP4M1 and the YEVM sequence of the lysosomal membrane protein CD63 (155740). Hirst et al. (1999) concluded that, like the other AP complexes, AP4 is involved in the recognition and sorting of cargo protein with tyrosine-based motifs.

By pull-down, immunoprecipitation, and yeast 2-hybrid analyses, Mattera et al. (2020) showed that AP4 interacted with an FTS (AKTIP; 608483)-HOOK-FHIP (FHF) complex containing FHIP (FHIP1B; 620229), FTS, HOOK1 (607820), HOOK2 (607824), and HOOK3 (607825). The interaction was mediated by direct binding between the mu-4 subunit of AP4 and the HOOK1 and HOOK2 subunits of FHF. Deletion mapping revealed that 2 coiled-coiled domains in HOOK1 were necessary and sufficient for interaction with mu-4, as well as with HOOK1 and HOOK3. HOOK2 and AP4 colocalized in the perinuclear area of Hela cells. Knockdown of FHF subunits resulted in dispersal of AP4 and ATG9A (612204) from the perinuclear region toward the periphery in Hela cells, indicating that the FHF complex interacted with AP4 to mediate perinuclear distribution of AP4 and its cargo, ATG9A. Moreover, dispersal of ATG9A affected autophagy in FHF-depleted cells.

Molecular Genetics

By linkage analysis followed by candidate gene sequencing of a consanguineous Moroccan family with spastic paraplegia and severe mental retardation (SPG50; 612936), Verkerk et al. (2009) identified a homozygous mutation in the AP4M1 gene (602296.0001). Verkerk et al. (2009) postulated that the genetic defect results in abnormal cycling of glutamate receptors, mimicking glutamate-mediated perinatal white matter injury.

By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a missense mutation in the AP4M1 gene (602296.0002) in affected members of a family (M004) segregating SPG50.

In affected members of 2 unrelated consanguineous Turkish families with SPG50, Tuysuz et al. (2014) identified 2 different homozygous truncating mutations in the AP4M1 gene (R338X, 602296.0003 and R318X, 602296.0004). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.

Animal Model

In mouse embryos, Verkerk et al. (2009) demonstrated Ap4m1 expression in all ventricular zones at different stages, suggesting a role in cerebral and cerebellar development. The localization corresponded to brain areas characterized by neuroglial progenitor proliferation, suggesting that an AP4M1 mutation might affect neurons as well as oligodendrocytes.

ALLELIC VARIANTS 4 Selected Examples):

.0001 SPASTIC PARAPLEGIA 50, AUTOSOMAL RECESSIVE

AP4M1, IVS14DS, G-T, +1
SNP: rs2134233729, ClinVar: RCV000007774

In affected members of a consanguineous Moroccan family with autosomal recessive spastic paraplegia-50 (SPG50; 612936) and severe mental retardation, Verkerk et al. (2009) identified a homozygous G-to-T transversion in intron 14 of the AP4M1 gene (1137+1G-T), resulting in the skipping of exon 14 and a significantly decreased amount of normal AP4M1 protein.

.0002 SPASTIC PARAPLEGIA 50, AUTOSOMAL RECESSIVE

AP4M1, GLU193LYS
SNP: rs387906838, ClinVar: RCV000023191, RCV001849279, RCV002272028

In a family (M004) in which 2 of 5 children of first-cousin parents had spastic paraplegia-50 (SPG50; 612936), characterized by severe intellectual disability, microcephaly, and spastic paraplegia, Najmabadi et al. (2011) identified homozygosity for a causative G-to-A transition at genomic coordinate chr7:99,539,684 (NCBI36) (chr7.99,539,684G-A, NCBI36) in the AP4M1 gene, resulting in a glu193-to-lys (E193K) substitution.

.0003 SPASTIC PARAPLEGIA 50, AUTOSOMAL RECESSIVE

AP4M1, ARG338TER
SNP: rs146262009, gnomAD: rs146262009, ClinVar: RCV000191922, RCV001849336, RCV003227707

In 2 sisters (family 1), born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-50 (SPG50; 612936), Tuysuz et al. (2014) identified a homozygous c.1012C-T transition (chr7.99,541,837C-T, NCBI36) in exon 13 of the AP4M1 gene, resulting in an arg338-to-ter (R338X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The mutation occurred in the mu homology domain and was not found in the dbSNP (build 131) or 1000 Genomes Project databases, or in control chromosomes. Functional studies of the variant and studies of patient cells were not performed.

.0004 SPASTIC PARAPLEGIA 50, AUTOSOMAL RECESSIVE

AP4M1, ARG318TER
SNP: rs730882249, gnomAD: rs730882249, ClinVar: RCV000162190, RCV000191923, RCV001529845, RCV001849324, RCV003390861

In 2 sibs (family 2), born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-50 (SPG50; 612936), Tuysuz et al. (2014) identified a homozygous c.952C-T transition (chr7.99,541,540C-T, NCBI36) in exon 12 of the AP4M1 gene, resulting in an arg318-to-ter (R318X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The mutation occurred in the mu homology domain and was not found in the dbSNP (build 131) or 1000 Genomes Project databases, or in control chromosomes. Functional studies of the variant and studies of patient cells were not performed.

REFERENCES

  1. Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S.AP-4, a novel protein complex related to clathrin adaptors. J. Biol. Chem. 274: 7278-7285, 1999. [PubMed: 10066790] [Full Text: https://doi.org/10.1074/jbc.274.11.7278\]
  2. Gross, M. B.Personal Communication. Baltimore, Md. 1/31/2023.
  3. Hirst, J., Bright, N. A., Rous, B., Robinson, M. S.Characterization of a fourth adaptor-related protein complex. Molec. Biol. Cell 10: 2787-2802, 1999. [PubMed: 10436028] [Full Text: https://doi.org/10.1091/mbc.10.8.2787\]
  4. Mattera, R., Williamson, C. D., Ren, X., Bonifacino, J. S.The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Molec. Biol. Cell 31: 963-979, 2020. [PubMed: 32073997] [Full Text: https://doi.org/10.1091/mbc.E19-11-0658\]
  5. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423\]
  6. Tuysuz, B., Bilguvar, K., Kocer, N., Yalcinkaya, C., Caglayan, O., Gul, E., Sahin, S., Comu, S., Gunel, M.Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. Am. J. Med. Genet. 164A: 1677-1685, 2014. [PubMed: 24700674] [Full Text: https://doi.org/10.1002/ajmg.a.36514\]
  7. Verkerk, A. J. M. H., Schot, R., Dumee, B., Schellekens, K., Swagemakers, S., Bertoli-Avella, A. M., Lequin, M. H., Dudink, J., Govaert, P., van Zwol, A. L., Hirst, J., Wessels, M. W., and 9 others.Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am. J. Hum. Genet. 85: 40-52, 2009. [PubMed: 19559397] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.004\]
  8. Wang, X., Kilimann, M. W.Identification of two new mu-adaptin-related proteins, mu-ARP1 and mu-ARP2. FEBS Lett. 402: 57-61, 1997. [PubMed: 9013859] [Full Text: https://doi.org/10.1016/s0014-5793(96)01500-1\]

Contributors:

Matthew B. Gross - updated : 01/31/2023
Bao Lige - updated : 01/31/2023
Cassandra L. Kniffin - updated : 9/23/2015
Ada Hamosh - updated : 1/6/2012
Cassandra L. Kniffin - updated : 7/28/2009
Patricia A. Hartz - updated : 9/19/2002

Creation Date:

Patti M. Sherman : 1/29/1998

Edit History:

mgross : 01/31/2023
mgross : 01/31/2023
carol : 07/29/2021
alopez : 09/25/2015
alopez : 9/25/2015
ckniffin : 9/23/2015
carol : 4/24/2012
ckniffin : 4/24/2012
carol : 1/6/2012
terry : 1/6/2012
wwang : 8/11/2009
ckniffin : 7/28/2009
terry : 3/3/2005
mgross : 9/19/2002
carol : 10/2/2000
terry : 6/3/1998
dholmes : 1/29/1998