Alternative titles; symbols
HGNC Approved Gene Symbol: AP1B1
SNOMEDCT: 403780007;
Cytogenetic location: 22q12.2 Genomic coordinates (GRCh38) : 22:29,327,680-29,388,570 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.2 | Keratitis-ichthyosis-deafness syndrome, autosomal recessive | 242150 | Autosomal recessive | 3 |
Adaptins are essential for the formation of adaptor complexes of clathrin-coated vesicles (CCVs). Adaptins interact with the cytoplasmic domains of membrane-spanning receptors in the course of their endocytic/exocytic transport. They represent 1 of at least 4 components of intracellular transport and receptor downregulation pathways, the others being alpha/gamma-adaptins, receptors, and ligand molecules. Beta-adaptins have a bipartite structure with invariant N-terminal and variable C-terminal domains. The former interact with the uniform component of coated vesicles, the clathrin lattice. In contrast, the C-terminal domain provides a set of recognition sequences for other proteins and therefore functions as part of a selector domain responsible for the specific entrapment of membrane-bound proteins in vesicles (summary by Peyrard et al., 1994).
A 140-kb homozygous deletion in 22q12 in a sporadic meningioma directed Peyrard et al. (1994) to the cloning and characterization of a new member of the human beta-adaptin gene family, which was named BAM22 for 'beta-adaptin-meningioma-chromosome 22.' The BAM22 gene was totally inactivated in the tumor with homozygous deletion. Northern blot analysis of 70 sporadic meningiomas showed specific loss of expression in 8 tumors, suggesting inactivation of BAM22. Based on this, Peyrard et al. (1994) suggested that BAM22 is a second chromosome 22 locus important in meningioma development and second in importance to the NF2 gene (607379), which is mutant in neurofibromatosis type II (101000). The likelihood that multiple loci on chromosome 22 are involved in the oncogenesis of meningioma is suggested by the facts that monosomy 22 is observed in as many as 65% of tumors (Zankl and Zang, 1980); some meningiomas have chromosome 22 deletions not encompassing the NF2 gene region and do not show mutations in the NF2 gene; and constitutional ring chromosome 22 has been observed in young patients with multiple tumors (Arinami et al., 1986; Petrella et al., 1993).
Boyden et al. (2019) stained a donor control skin biopsy with anti-AP1B1 and observed cytoplasmic localization in all layers of the epidermis.
Peyrard et al. (1994) identified the BAM22 gene within chromosome 22q12.
Peyrard et al. (1996) described the genomic structure of the human beta-adaptin gene BAM22. The gene contains 22 exons spanning over 100 kb.
Doray et al. (2002) demonstrated that the Golgi-localized, gamma-ear-containing adenosine diphosphate ribosylation factor-binding proteins (GGA1, 606004 and GGA3, 606006) and the coat protein adaptor protein-1 (AP-1) complex (see AP1G2, 603534) colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 (see CSNK2A1, 115440) that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et al. (2002) demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (see 154540) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles.
In 2 sibs and an unrelated boy with autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR; 242150), Alsaif et al. (2019) identified homozygosity for a microdeletion (600157.0001) and a splicing mutation (600157.0002), respectively, in the AP1B1 gene.
From a large cohort of individuals with keratinization disorders with and without associated syndromic features, Boyden et al. (2019) identified 2 unrelated patients with KIDAR syndrome and biallelic mutations in the AP1B1 gene: a 33-year-old man who was compound heterozygous for a missense mutation (C144R; 600157.0003) and a 1-bp deletion (600157.0004), and an 11-month-old Ashkenazi Jewish girl who was homozygous for a nonsense mutation (E792X; 600157.0005).
In a 7-year-old Turkish girl with ichthyosis, erythroderma, deafness, and developmental delay, Meric et al. (2021) identified homozygosity for a missense mutation in the AP1B1 gene (L223P; 600157.0006) that segregated with disease in the family.
In a 2.5-year-old German girl with ichthyosis, erythroderma, deafness, and developmental delay, Vornweg et al. (2021) identified compound heterozygosity for a previously reported 1-bp deletion (600157.0004) and a missense mutation (R108W; 600157.0007) in the AP1B1 gene. Her healthy nonconsanguineous parents were each heterozygous for 1 of the variants.
In a 2-year-old Japanese boy with ichthyosis, developmental delay, and deafness, Ito et al. (2021) identified compound heterozygosity for nonsense mutations in the AP1B1 gene, Q618X (600157.0008) and Q866X (600157.0009). His unaffected parents were each heterozygous for 1 of the variants.
In a 6.5-year-old Iranian boy with KIDAR, Faghihi et al. (2022) identified homozygosity for a nonsense mutation in the AP1B1 gene (Y421X; 600157.0010). His first-cousin unaffected parents were heterozygous for the mutation, which was not found in public variant databases.
Exclusion Studies
Peyrard et al. (1996) analyzed 7 exons of the BAM22 gene for sporadic mutations in 110 sporadic meningiomas (see 607174) and failed to detect point mutations. The authors suggested that mutations in the promoter region of the gene may be important in generating meningiomas. They also considered the possibility that the 140-kb region on chromosome 22 involved in homozygous deletions in meningiomas may contain another candidate tumor suppressor gene.
In a 4.3-year-old girl of Pakistani origin and her 1.5-year-old brother (patients 1 and 2) with ichthyotic erythroderma, profound sensorineural deafness, and ectropion (KIDAR; 242150), Alsaif et al. (2019) identified homozygosity for a 75-kb deletion (chr22.29,758,984-29,815,476, GRCh37) that removes a putative promoter as well as the first 2 exons of AP1B1. Their unaffected second-cousin parents were heterozygous for the deletion. RT-PCR of patient fibroblasts showed complete absence of AP1B1 transcript. Both sibs had low plasma copper and ceruloplasmin levels, and analysis of patient dermal fibroblasts showed dramatic perturbation of trafficking of a key copper transporter, ATP7A (300011), which showed random colocalization with the trans-Golgi network compared to the nearly perfect colocalization seen in controls. In addition, proteomic analysis of clathrin (see 118955)-coated vesicles showed that AP1B1 was the only component consistently reduced in patient fibroblasts compared to controls, suggesting that AP1B1 deficiency results in a specific defect in CCVs.
In a 4.5-year-old Saudi boy (patient 3) with ichthyotic erythroderma and associated palmoplantar hyperkeratosis as well as profound deafness (KIDAR; 242150), Alsaif et al. (2019) identified homozygosity for a splicing mutation (c.38-1G-A, NM_001127) in intron 2 of the AP1B1 gene that results in an aberrant transcript with a 1-bp deletion (r.40del), predicted to lead to a premature termination codon (Glu14ArgfsTer5). His unaffected parents and 3 unaffected sibs were heterozygous for the mutation. The proband had low plasma copper and ceruloplasmin levels, and analysis of his dermal fibroblasts showed dramatic perturbation of trafficking of a key copper transporter, ATP7A (300011), which showed random colocalization with the trans-Golgi network compared to the nearly perfect colocalization seen in controls. In addition, proteomic analysis of clathrin (see 118955)-coated vesicles showed that AP1B1 was the only component consistently reduced in patient fibroblasts compared to controls, suggesting that AP1B1 deficiency results in a specific defect in CCVs.
In a 33-year-old man (patient 424) with congenital ichthyosiform erythroderma, palmoplantar keratoderma, deafness, and corneal scarring causing nearly complete vision loss (KIDAR; 242150), Boyden et al. (2019) identified compound heterozygosity for a c.430T-C transition (c.430T-C, NM_001127.3) in the AP1B1 gene, resulting in a cys144-to-arg (C144R) substitution at a highly conserved residue, and a 1-bp deletion (c.2335delC; 600157.0004), causing a frameshift predicted to result in a premature termination codon (Leu779SerfsTer26). His unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the 1-bp deletion (c.2335delC, NM_001127.3) in the AP1B1 gene, causing a frameshift predicted to result in a premature termination codon (Leu779SerfsTer26), that was found in compound heterozygous state in a 33-year-old man (patient 424) with keratitis-ichthyosis-deafness syndrome (KIDAR; 242150) by Boyden et al. (2019), see 600157.0003.
In a 2.5-year-old German girl with ichthyosis, erythroderma, deafness, and developmental delay, Vornweg et al. (2021) identified compound heterozygosity for mutations in the AP1B1 gene: one was this previously reported 1-bp deletion, which they designated c.2254delC (c.2254delC, ENST00000317368.7), causing a frameshift predicted to result in a premature termination codon (Leu752SerfsTer26); and the other was a c.322C-T transition, resulting in an arg108-to-trp (R108W; 600157.0007) substitution at a highly conserved residue within a putative protein-binding region. Her healthy nonconsanguineous parents were each heterozygous for 1 of the variants. RT-PCR in patient keratinocytes detected the missense mutation but not the frameshift mutation; however, analysis of patient epidermis and isolated keratinocytes showed complete loss of AP1B1.
In an 11-month-old Ashkenazi Jewish girl (patient 1325) with congenital ichthyosiform erythroderma, palmoplantar keratoderma, deafness, and photophobia (KIDAR; 242150), Boyden et al. (2019) identified homozygosity for a c.2374G-T transversion (c.2374G-T, NM_001127.3) in the AP1B1 gene, resulting in a glu792-to-ter (E792X) substitution. Her unaffected second-cousin once-removed parents were both heterozygous for the mutation. Electron microscopy of patient keratinocytes revealed accumulation of electron-dense vesicles of varied size and density within the proliferative layers of the epidermis. Transduction of patient primary keratinocytes with wildtype AP1B1 rescued the vesicular defects, and the cells were indistinguishable from control keratinocytes.
In a 7-year-old Turkish girl with ichthyosis, deafness, and developmental delay, (KIDAR; 242150), Meric et al. (2021) identified homozygosity for a c.668T-C transition (c.668T-C, NM_001127) in exon 6 of the AP1B1 gene, resulting in a leu223-to-pro (L223P) substitution at a highly conserved residue. Her unaffected first-cousin parents were heterozygous for the mutation.
For discussion of the c.322C-T transition (c.322C-T, ENST00000317368.7) in the AP1B1 gene, resulting in an arg108-to-trp (R108W) substitution, that was found in compound heterozygous state in a 2.5-year-old German girl with KIDAR syndrome (242150) by Vornweg et al. (2021), see 600157.0004.
In a 2-year-old Japanese boy with ichthyosis, deafness, and developmental delay (KIDAR; 242150), Ito et al. (2021) identified compound heterozygosity for nonsense mutations in the AP1B1 gene: c.1852C-T and c.2596C-T transitions, resulting in gln618-to-ter (Q618X) and gln866-to-ter (Q866X; 600157.0009) substitutions, respectively. His unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the c.2596C-T transition in the AP1B1 gene, resulting in a gln866-to-ter (Q866X) substitution, that was found in compound heterozygous state in a 2-year-old Japanese boy with KIDAR syndrome (242150) by Ito et al. (2021), see 600157.0008.
In a 6.5-year-old Iranian boy with keratitis, ichthyosis, hearing loss, and developmental delay (KIDAR; 242150), Faghihi et al. (2022) identified homozygosity for a c.1263C-A transversion (c.1263C-A, NM_001127.4) in the AP1B1 gene, resulting in a tyr421-to-ter (Y421X) substitution. His first-cousin parents were heterozygous for the mutation, which was not found in the Iranome, GME, TogoVar, or gnomAD databases.
Alsaif, H. S., Al-Owain, M., Barrios-Llerena, M. E., Gosadi, G., Binamer, Y., Devadason, D., Ravenscroft, J., Suri, M., Alkuraya, F. S. Homozygous loss-of-function mutations in AP1B1, encoding beta-1 subunit of adaptor-related protein complex 1, cause MEDNIK-like syndrome. Am. J. Hum. Genet. 105: 1016-1022, 2019. [PubMed: 31630791] [Full Text: https://doi.org/10.1016/j.ajhg.2019.09.020]
Arinami, T., Kondo, I., Hamaguchi, H., Nakajima, S. Multifocal meningiomas in a patient with a constitutional ring chromosome 22. J. Med. Genet. 23: 178-180, 1986. [PubMed: 3712397] [Full Text: https://doi.org/10.1136/jmg.23.2.178]
Boyden, L. M., Atzmony, L., Hamilton, C., Zhou, J., Lim, Y. H., Hu, R., Pappas, J., Rabin, R., Ekstien, J., Hirsch, Y., Prendiville, J., Lifton, R. P., Ferguson, S., Choate, K. A. Recessive mutations in AP1B1 cause ichthyosis, deafness, and photophobia. Am. J. Hum. Genet. 1023-1029, 2019. [PubMed: 31630788] [Full Text: https://doi.org/10.1016/j.ajhg.2019.09.021]
Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science 297: 1700-1703, 2002. [PubMed: 12215646] [Full Text: https://doi.org/10.1126/science.1075327]
Faghihi, F., Khamirani, H. J., Zoghi, S., Kamal, N., Yeganeh, B. S., Dianatpour, M., Bagher Tabei, S. M., Dastgheib, S. A. Phenotypic spectrum of autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR) due to mutations in AP1B1. Europ. J. Med. Genet. 65: 104449, 2022. [PubMed: 35144013] [Full Text: https://doi.org/10.1016/j.ejmg.2022.104449]
Ito, Y., Takeichi, T., Igari, S., Mori, T., Ono, A., Suyama, K., Takeuchi, S., Muro, Y., Ogi, T., Hosoya, M., Yamamoto, T., Akiyama, M. MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1. J. Europ. Acad. Derm. Venereol. 35: e345-e347, 2021. [PubMed: 33349978] [Full Text: https://doi.org/10.1111/jdv.17098]
Meric, R., Ercan-Sencicek, A. G., Uludag Alkaya, D., Sahin, Y., Sar, M., Bilguvar, K., Tuysuz, B. A patient with mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia syndrome caused by AP1B1 gene variant. Clin. Dysmorph. 30: 54-57, 2021. [PubMed: 32969855] [Full Text: https://doi.org/10.1097/MCD.0000000000000350]
Petrella, R., Levine, S., Wilmot, P. L., Ashar, K. D., Casamassima, A. C., Shapiro, L. R. Multiple meningiomas in a patient with constitutional ring chromosome 22. Am. J. Med. Genet. 47: 184-186, 1993. [PubMed: 8213904] [Full Text: https://doi.org/10.1002/ajmg.1320470211]
Peyrard, M., Fransson, I., Xie, Y.-G., Han, F.-Y., Ruttledge, M. H., Swahn, S., Collins, J. E., Dunham, I., Collins, V. P., Dumanski, J. P. Characterization of a new member of the human beta-adaptin gene family from chromosome 22q12, a candidate meningioma gene. Hum. Molec. Genet. 3: 1393-1399, 1994. [PubMed: 7987321] [Full Text: https://doi.org/10.1093/hmg/3.8.1393]
Peyrard, M., Pan, H.-Q., Kedra, D., Fransson, I., Swahn, S., Hartman, K., Clifton, S. W., Roe, B. A., Dumanski, J. P. Structure of the promoter and genomic organization of the human beta-prime-adaptin gene (BAM22) from chromosome 22q12. Genomics 36: 112-117, 1996. [PubMed: 8812422] [Full Text: https://doi.org/10.1006/geno.1996.0431]
Vornweg, J., Glaser, S., Ahmad-Anwar, M., Zimmer, A. D., Kuhn, M., Horer, S., Korenke, G. C., Grothaus, J., Ott, H., Fischer, J. Identification of compound heterozygous mutations in AP1B1 leading to the newly described recessive keratitis-ichthyosis-deafness (KIDAR) syndrome. Brit. J. Derm. 184: 1190-1192, 2021. [PubMed: 33452671] [Full Text: https://doi.org/10.1111/bjd.19815]
Zankl, H., Zang, K. D. Correlations between clinical and cytogenetical data in 180 human meningiomas. Cancer Genet. Cytogenet. 1: 351-356, 1980.