Alternative titles; symbols
HGNC Approved Gene Symbol: BLOC1S5
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38) : 6:8,013,567-8,064,414 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.3 | Hermansky-Pudlak syndrome 11 | 619172 | Autosomal recessive | 3 |
The muted (mu) mouse is a model for Hermansky-Pudlak Syndrome (HPS; 203300). Mice with mutations in the muted gene have light eyes at birth and fur of a muted brown shade.
Zhang et al. (2002) identified and cloned the mouse muted gene. Full-length muted cDNA encodes a deduced 185-amino acid protein. Northern blot analysis revealed ubiquitous expression of a 1.8-kb transcript in normal mice, with higher levels in brain, bone marrow, kidney, and liver and lower levels in skeletal muscle. By transfection of mouse melanocytes with epitope-tagged muted constructs, Zhang et al. (2002) found muted protein in vesicles distributed throughout the cell body and dendrites. Comparison with bright field images established that the vesicles were not coincident with melanosomes. Transfected COS-7 cells exhibited a similar vesicular pattern throughout the cell body.
Zhang et al. (2002) cloned the human muted gene by RT-PCR, 5-prime RACE, and 3-prime RACE of human placenta mRNA. The deduced protein has 187 amino acids and contains a possible vacuolar targeting motif (TLPK) that is absent from the mouse sequence. The mouse and human proteins share 76% sequence identity.
By Western blot analysis of wildtype mouse fibroblasts, Falcon-Perez et al. (2002) detected expression of a 23-kD muted protein.
Zhang et al. (2002) determined that the mouse muted gene contains 5 exons and spans 52 kb. The genomic structure of the human muted gene is similar.
Zhang et al. (2002) mapped the mouse muted gene to a segment of chromosome 13 that shows homology of synteny to human chromosome 6p24-p23. By genomic sequence analysis, they mapped the human gene to chromosome 6p25.1-p24.3.
By coimmunoprecipitation and immunodepletion experiments of mouse skin fibroblasts, Falcon-Perez et al. (2002) identified muted as a component of BLOC1 (biogenesis of lysosome-related organelles complex-1), which also contains pallidin (PLDN; 604310). A yeast 2-hybrid screen found no direct interaction between muted and pallidin, but pallidin was found to interact with itself.
In 2 unrelated women with Hermansky-Pudlak syndrome-11 (HPS11; 619172), who were negative for mutation in known HPS-associated genes, Pennamen et al. (2020) identified homozygosity for deletions in the BLOC1S5 gene: patient 1 had an intragenic deletion involving exons 3 and 4 (607289.0001) and patient 2 had a 1-bp deletion (607289.0002). Functional analysis of mutant BLOC1S5 from patient 1 demonstrated that the mutant protein was unable to restore BLOC1 stability or function in melanogenesis and protein sorting in murine melanocytes lacking the orthologous BLOC1S5/muted protein, suggesting that this represents a loss-of-function variant.
Zhang et al. (2002) noted that 'muted' (mu) mice show hypopigmentation, hemorrhaging, and early death due to lung abnormalities. Ultrastructural examination revealed that the eyes of adult muted mice had reduced total number of melanosomes within the retinal pigment epithelium and significantly reduced number within the choroid. Northern blot analysis revealed a lack of muted transcript in tissues obtained from muted mice; intermediate amounts of transcript were detected in heterozygous mice. Zhang et al. (2002) determined that expression of muted was abrogated in a mutant allele containing an insertion of an early transposon (ETn) retrotransposon. Expression was likewise lost in the muted(J) allele, which has a 1-bp deletion within the coding region. The mu mouse is a model for Hermansky-Pudlak syndrome (HPS; see 203300). The mu gene encodes a ubiquitously expressed transcript, specifying a predicted 185-amino acid protein, whose expression is abrogated in the mu allele by insertion of an early transposon (ETn) retrotransposon. Mu mice demonstrated structurally aberrant melanosomes in the eyes; the muted protein was localized by immunofluorescence within vesicles of the cell body and dendrites of transfected melanocytes, suggesting a role of the mu gene in vesicle trafficking. The mu gene was present only in mice and humans among analyzed genomes, and BACs containing the human homolog were previously localized to chromosome 6p24.3-p25.1. The authors concluded that the mu gene is a member of a novel gene set found among higher eukaryotes which regulates the synthesis/function of highly specialized subcellular organelles such as melanosomes and platelet dense granules.
Falcon-Perez et al. (2002) detected no muted protein in fibroblasts from muted mice.
In a 20-year-old French woman with mild oculocutaneous albinism and a bleeding diathesis (HPS11; 619172), Pennamen et al. (2020) identified homozygosity for a 19,063-bp deletion (c.196-678_384+3483del, NM_201280.2) encompassing exons 3 and 4 of the BLOC1S5 gene. The deletion was present in heterozygosity in her unaffected parents. The breakpoints were located within a region of 100% homology in introns 2 and 4, suggesting that the deletion resulted from a nonallelic homologous recombination event. Western blot analysis of the patient's platelet lysates showed reduced or absent levels of pallidin (BLOC1S6; 604310) and dysbindin (DTNBP1; 607145) compared to controls. Functional analysis demonstrated that the mutant protein was unable to restore BLOC1 stability or function in melanogenesis and protein sorting in murine melanocytes lacking the orthologous BLOC1S5/muted protein, suggesting that this represents a loss-of-function variant.
In a 39-year-old Slovenian woman with mild oculocutaneous albinism and a bleeding diathesis (HPS11; 619172), Pennamen et al. (2020) identified homozygosity for a 1-bp deletion (c.345del, NM_201280.2) in exon 4 of the BLOC1S5 gene, causing a frameshift predicted to result in a premature termination codon (Val116SerfsTer19). Parental DNA was unavailable for segregation analysis.
Falcon-Perez, J. M., Starcevic, M., Gautam, R., Dell'Angelica, E. C. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules. J. Biol. Chem. 277: 28191-28199, 2002. [PubMed: 12019270] [Full Text: https://doi.org/10.1074/jbc.M204011200]
Pennamen, P., Le, L., Tingaud-Sequeira, A., Fiore, M., Bauters, A., Van Duong Beatrice, N., Coste, V., Bordet, J. C., Plaisant, C., Diallo, M., Michaud, V., Trimouille, A., Lacombe, D., Lasseaux, E., Delevoye, C., Picard, F. M., Delobel, B., Marks, M. S., Arveiler, B. BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome. Genet. Med. 22: 1613-1622, 2020. [PubMed: 32565547] [Full Text: https://doi.org/10.1038/s41436-020-0867-5]
Zhang, Q., Li, W., Novak, E. K., Karim, A., Mishra, V., Kingsmore, S. F., Roe, B. A., Suzuki, T., Swank, R. T. The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking. Hum. Molec. Genet. 11: 697-706, 2002. [PubMed: 11912185] [Full Text: https://doi.org/10.1093/hmg/11.6.697]