Alternative titles; symbols
HGNC Approved Gene Symbol: EXPH5
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38) : 11:108,505,435-108,607,536 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.3 | Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive | 615028 | Autosomal recessive | 3 |
EXPH5 is a RAB27 (RAB27A; 603868) effector implicated in intracellular vesicular trafficking and secretion. EXPH5 supports lysosome-mediated trafficking required for epidermal differentiation (Monteleon et al., 2019).
By sequencing clones obtained from a size-fractionated brain cDNA library, Ishikawa et al. (1998) cloned EXPH5, which they designated KIAA0624. The deduced protein contains 1,983 amino acids. RT-PCR detected highest EXPH5 expression in kidney, followed by lung, brain, liver, and ovary. Little to no expression was detected in skeletal muscle or spleen. Kuroda et al. (2002) showed that EXPH5, which they called SLAC2B, contains an N-terminal synaptotagmin (see SYT1, 185605)-like homology domain (SHD).
By semiquantitative RT-PCR, McGrath et al. (2012) demonstrated expression of EXPH5 in skin, muscle, heart, and brain. No amplification was achieved from kidney, liver, or lung.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the EXPH5 gene to chromosome 11.
Gross (2021) mapped the EXPH5 gene to chromosome 11q22.3 based on an alignment of the EXPH5 sequence (GenBank BC113119) with the genomic sequence (GRCh38).
Using a protein pull-down assay, Kuroda et al. (2002) found that the isolated N-terminal SHD of human SLAC2B and mouse Slp2a (SYTL2; 612880) bound RAB27A, but no other small GTP-binding protein examined. Coimmunoprecipitation analysis confirmed that full-length SLAC2B and SLP2A interacted specifically with RAB27A following transfection of COS-7 cells.
McGrath et al. (2012) examined the cytoskeletal architecture of keratinocytes from patients with a truncating mutation in the EXPH5 gene (612878.0001) compared to SLAC2B-knockdown control keratinocytes, and observed disruption of the keratin filament network and more cortically distributed F-actin in both compared to wildtype. Keratinocyte adhesion assays demonstrated significantly reduced cell adhesion in both mutant and knockdown keratinocytes compared to controls. SLAC2B was also observed to colocalize with RAB27B (603869) and beta-4-integrin (147557) to early adhesion initiation sites in spreading normal keratinocytes.
Using knockdown analysis, Monteleon et al. (2019) showed that EXPH5 supported delivery of lysosome-related organelles (LROs) to the keratinocyte plasma membrane and was essential for differentiation of human keratinocytes. The differentiation defect in EXPH5-knockdown keratinocytes with lysosomal defects was rescued in trans by coculturing them with normal keratinocytes. The results demonstrated that keratinocyte differentiation is not a purely cell-autonomous process and that it is promoted by secreted LROs from adjacent differentiating keratinocytes through cell-cell communication mediated via lysosome-mediated exocytosis.
In 3 affected sibs from a consanguineous Iraqi family segregating autosomal recessive inherited skin fragility (EBS4; 615028) who were negative for mutation in the KRT5 (148040) and KRT14 (148066) genes, McGrath et al. (2012) identified homozygosity for a 1-bp deletion (612878.0001) in the EXPH5 gene. McGrath et al. (2012) noted that the collective clinicopathologic features in these patients were not diagnostic for any particular subtype of epidermolysis bullosa (see, e.g., 131760).
Pigors et al. (2014) sequenced the EXPH5 gene in a cohort of 35 patients with clinically suspected epidermolysis bullosa simplex (EBS) who were negative for mutation in the KRT5 and KRT14 genes, and identified a 2-year-old German girl who was compound heterozygous for 1-bp deletions in EXPH5 (612878.0002 and 612878.0003).
In a 4-year-old Caucasian boy with skin fragility, who was negative for mutation in known intraepidermal fragility-associated genes, Liu et al. (2014) sequenced the EXPH5 gene and identified compound heterozygosity for a 1-bp duplication (612878.0004) and a nonsense mutation (S750X; 612878.0005).
In a 9-year-old Pakistani boy with skin fragility from birth that improved with age, Rashidghamat et al. (2016) identified homozygosity for a nonsense mutation in the EXPH5 gene (L1217X; 612878.0006).
In a 3-year-old Israeli Arab Christian girl who was born with skin blistering and later had skin fragility and erosions, who was negative for mutation in the KRT5 and KRT14 genes, Malchin et al. (2016) sequenced the EXPH5 gene and identified homozygosity for a 1-bp deletion (612878.0007). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in population-matched controls or in public variant databases.
In a teenaged Moroccan girl with skin fragility and blistering that ameliorated with age, Turcan et al. (2016) performed next-generation sequencing using a panel of 33 epidermolysis bullosa-associated genes and identified homozygosity for a nonsense mutation in the EXPH5 gene (S1306X; 612878.0008). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in public variant databases.
In a 3-year-old Italian girl with epidermolysis bullosa simplex, Diociaiuti et al. (2020) identified heterozygosity for a previously reported 1-bp deletion (612878.0001) in exon 6 of the EXPH5 gene.
In 3 affected sibs from a consanguineous Iraqi family with inherited skin fragility (EBS4; 615028), McGrath et al. (2012) identified homozygosity for a 1-bp deletion (c.5786delC, NM_015065.2) in exon 6 of the EXPH5 gene, causing a frameshift predicted to result in a premature termination codon truncating the protein by 52 residues (Pro1929LeufsTer8). The mutation segregated with disease in the family and was not found in 200 control chromosomes from mixed Iraqi, Iranian, Kuwaiti, and Omani populations. Patient keratinocytes showed disruption of the keratin filament network and more cortically distributed F-actin as well as significantly reduced cell adhesion compared to wildtype keratinocytes.
In a 3-year-old Italian girl with epidermolysis bullosa simplex, Diociaiuti et al. (2020) identified homozygosity for the c.5786delC mutation in the EXPH5 gene. Her unaffected consanguineous parents were heterozygous for the mutation.
In a 2-year-old German girl with epidermolysis bullosa simplex (EBS4; 615028), Pigors et al. (2014) identified compound heterozygosity for 1-bp deletions in exon 6 of the EXPH5 gene, both causing frameshifts predicted to result in premature termination codons: the first was c.1395delC (c.1395delC, NM_015065.2), resulting in Phe466LeufsTer44, and the second was c.2897delC (612878.0003), resulting in Pro966LeufsTer11. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 100 German controls. No biopsy material was available for functional analysis.
For discussion of the 1-bp deletion (c.2897delC, NM_015065.2) in exon 6 of the EXPH5 gene, causing a frameshift predicted to result in a premature termination codon (Pro966LeufsTer11), that was found in compound heterozygous state in a 2-year-old German girl with epidermolysis bullosa simplex (EBS4; 615028) by Pigors et al. (2014), see 612878.0002.
In a 4-year-old Caucasian boy with epidermolysis bullosa simplex (EBS4; 615028), Liu et al. (2014) identified compound heterozygosity for a 1-bp duplication (c.1947dupC, NM_015065.2), causing a frameshift predicted to result in a premature termination codon (Pro649ProfsTer11), and a c.2249C-A transversion, resulting in a ser750-to-ter (S750X; 612878.0005) substitution. His unaffected parents were each heterozygous for 1 of the mutations. Immunostaining of patient skin revealed a complete absence of exophilin-5 within the epidermis.
For discussion of the c.2249C-A transversion (c.2249C-A, NM_015065.2) in the EXPH5 gene, resulting in a ser750-to-ter (S750X) substitution, that was found in compound heterozygous state in a 4-year-old Caucasian boy with epidermolysis bullosa simplex (EBS4; 615028) by Liu et al. (2014), see 612878.0004.
In a 9-year-old Pakistani boy with skin fragility at birth that improved with age (EBS4; 615028), Rashidghamat et al. (2016) identified homozygosity for a c.3650T-A transversion in exon 6 of the EXPH5 gene, resulting in a leu1217-to-ter (L1217X) substitution. His unaffected mother was heterozygous for the mutation; DNA was unavailable from his affected father who, like the proband, was born of first-cousin parents, or from the proband's affected younger brother. Exophilin-5 immunostaining was barely detectable in a shave biopsy of patient skin.
In a 3-year-old Israeli Arab Christian girl who was born with skin blistering and later had skin fragility and erosions (EBS4; 615028), Malchin et al. (2016) identified homozygosity for a 1-bp deletion (c.2542delC), causing a frameshift predicted to result in a premature termination codon (His848TrpfsTer5). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in 230 population-matched controls or in the ESP, NCBI, or 1000 Genomes Project databases.
In a teenaged Moroccan girl with autosomal recessive epidermolysis bullosa simplex (EBS4; 615028), Turcan et al. (2016) identified homozygosity for a c.3917C-G transversion (c.3917C-G, NM_015065.2) in exon 6 of the EXPH5 gene, resulting in a ser1306-to-ter (S1306X) substitution. Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in the Genome of the Netherlands, 1000 Genomes Project, or ExAC databases.
Diociaiuti, A., Pisaneschi, E., Rossi, S., Condorelli, A. G., Carnevale, C., Zambruno, G., El Hachem, M. Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: neonatal diagnosis of the first Italian case and literature review. J. Europ. Acad. Derm. Venereol. 34: e694-e697, 2020. [PubMed: 32176379] [Full Text: https://doi.org/10.1111/jdv.16372]
Gross, M. B. Personal Communication. Baltimore, Md. 9/28/2021.
Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 169-176, 1998. [PubMed: 9734811] [Full Text: https://doi.org/10.1093/dnares/5.3.169]
Kuroda, T. S., Fukuda, M., Ariga, H., Mikoshiba, K. The Slp homology domain of synaptotagmin-like proteins 1-4 and Slac2 functions as a novel Rab27A binding domain. J. Biol. Chem. 277: 9212-9218, 2002. [PubMed: 11773082] [Full Text: https://doi.org/10.1074/jbc.M112414200]
Liu, L., Mellerio, J. E., Martinez, A. E., McMillan, J. R., Aristodemou, S., Parsons, M., McGrath, J. A. Mutations in EXPH5 result in autosomal recessive inherited skin fragility. Brit. J. Derm. 170: 196-199, 2014. [PubMed: 24443915] [Full Text: https://doi.org/10.1111/bjd.12723]
Malchin, N., Sarig, O., Grafi-Cohen, M., Geller, S., Goldberg, I., Shani, A., Gat, A., Sprecher, E., Mashiah, J. A novel homozygous deletion in EXPH5 causes a skin fragility phenotype. Clin. Exp. Derm. 41: 915-918, 2016. [PubMed: 27730671] [Full Text: https://doi.org/10.1111/ced.12908]
McGrath, J. A., Stone, K. L., Begum, R., Simpson, M. A., Dopping-Hepenstal, P. J., Liu, L., McMillan, J. R., South, A. P., Pourreyron, C., McLean, W. H. I., Martinez, A. E., Mellerio, J. E., Parsons, M. Germline mutation in EXPH5 implicates the Rab27B effector protein Slac2-b in inherited skin fragility. Am. J. Hum. Genet. 91: 1115-1121, 2012. [PubMed: 23176819] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.012]
Monteleon, C. L., Lee, I. Y., Ridky, T. W. Exophilin-5 supports lysosome-mediated trafficking required for epidermal differentiation. J. Invest. Derm. 139: 2219-2222, 2019. [PubMed: 31082377] [Full Text: https://doi.org/10.1016/j.jid.2019.04.014]
Pigors, M., Schwieger-Briel, A., Leppert, J., Kiritsi, D., Kohlhase, J., Bruckner-Tuderman, L., Has, C. Molecular heterogeneity of epidermolysis bullosa simplex: contribution of EXPH5 mutations. J. Invest. Derm. 134: 842-845, 2014. [PubMed: 24005056] [Full Text: https://doi.org/10.1038/jid.2013.373]
Rashidghamat, E., Ozoemena, L., Liu, L., McGrath, J. A., Martinez, A. E., Mellerio, J. E. Mutations in EXPH5 underlie a rare subtype of autosomal recessive epidermolysis bullosa simplex. Brit. J. Derm. 174: 452-453, 2016. [PubMed: 26211931] [Full Text: https://doi.org/10.1111/bjd.14047]
Turcan, I., Pasmooij, A. M., Van den Akker, P. C., Lemmink, H., Sinke, R. J., Jonkman, M. F. Association of epidermolysis bullosa simplex with mottled pigmentation and EXPH5 mutations. JAMA Derm. 152: 1137-1141, 2016. [PubMed: 27384765] [Full Text: https://doi.org/10.1001/jamadermatol.2016.2268]