Alternative titles; symbols
HGNC Approved Gene Symbol: OBSL1
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:219,547,206-219,571,539 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | 3-M syndrome 2 | 612921 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Ishikawa et al. (1998) obtained a partial OBSL1 clone, which they designated KIAA0657. RT-PCR detected high expression in heart and ovary, moderate expression in brain, skeletal muscle, and testis, and low expression in all other tissues examined.
By searching protein and nucleotide databases for sequences similar to the N-terminal fibronectin domain of obscurin (608616), followed by PCR and 5-prime RACE of a heart cDNA library, Geisler et al. (2007) obtained full-length OBSL1 and several alternatively spliced products. The variants could be arranged in 3 main groups, A, B, or C, depending upon which of 3 alternative translation stop codons was used. The encoded proteins ranged in predicted molecular mass from 130 to 230 kD. The longest transcript, OBSL1-A, encodes a protein with 4 tandem N-terminal immunoglobulin (Ig)-like domains, a central fibronectin domain, and 13 C-terminal Ig domains. The shorter splice variants encode proteins with fewer C-terminal Ig domains, and the shortest, OBSL1-B, contains only 3 C-terminal Ig domains. Northern blot analysis detected a 6-kb transcript (OBSL1-A) highly expressed in heart and more weakly in skeletal muscle and testis. A 3.3-kb transcript (OBSL1-B) was detected in most tissues, with highest expression in heart and placenta. Other variants ranging from about 4.9 to 5.8 kb were detected in several noncardiac tissues. Western blot analysis of adult human and rat heart lysates detected predominant expression of OBSL1-A at an apparent molecular mass of about 230 kD. Several other bands were more predominant in human heart lysates than in those from rat. Immunohistochemical analysis of isolated rat cardiac myocytes localized Obsl1 to the intercalated disc, to the perinuclear region, and overlying the Z lines and, to a lesser extent, the M bands. Accumulation of Obsl1 was noted between adjacent but not yet fused myofibrils. In these areas, Obsl1 was arranged in a linear or dotted pattern with accumulation overlying the Z lines. In cultured rat cardiac myocytes, the localization of Obsl1 was dynamic. The intracellular protein distribution of OBSL1 and its domain organization led Geisler et al. (2007) to propose that OBSL1 is a cytoskeletal adaptor.
Hanson et al. (2009) stated that the A, B, and C isoforms of OBSL1 contain 1,896, 1,401, and 1.025 amino acids, respectively.
Geisler et al. (2007) determined that the OBSL1 gene contains 22 exons and spans about 25 kb.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the OBSL1 gene to chromosome 2. Geisler et al. (2007) stated that the OBSL1 gene maps to chromosome 2q35.
In affected individuals from 10 unrelated families with 3M syndrome-2 (3M2; 612921), Hanson et al. (2009) identified homozygous or compound heterozygous mutations in the OBSL1 gene (see, e.g., 610991.0001-610991.0005). All of the mutations were truncating mutations within the first 6 exons of the gene and affected all known isoforms, resulting in complete loss of OBSL1. Thus, 3M syndrome-2 represents the null phenotype of human OBSL1. All patients had short stature, prominent heels, and a distinctive facial appearance with anteverted nares, fleshy tipped nose, frontal bossing, midface hypoplasia, and prominent heels, and were phenotypically indistinguishable from those with 3M syndrome-1 (3M1; 273750) which is due to mutations in the CUL7 gene (609577). Knockdown of OBSL1 via siRNAs in HEK cells led to a decrease in CUL7 levels, suggesting a role for OBSL1 in the maintenance of normal levels of CUL7. These findings suggested that the 2 proteins work in the same pathway that affects cell proliferation and human growth.
In a 16.5-year-old Turkish boy with 3M syndrome, Demir et al. (2013) identified homozygosity for a frameshift mutation in the OBSL1 gene (610991.0006).
In a 16-month-old Turkish girl with 3M syndrome, Keskin et al. (2017) identified homozygosity for the most prevalent mutation in the OBSL1 gene, a 1-bp duplication (610991.0001).
In affected members of 4 unrelated families of Asian origin with 3M syndrome-2 (3M2; 612921), Hanson et al. (2009) identified a homozygous 1-bp insertion (1273insA) in exon 3 of the OBSL1 gene, causing a frameshift predicted to result in a premature termination codon (Thr425AsnfsTer40). The mutation occurred near the N terminus and affected all OBSL1 isoforms, consistent with complete loss of protein function and a null phenotype. Two of the families were large consanguineous families with multiple affected individuals. Two additional probands with the disorder were compound heterozygous for the 1273insA mutation and another truncating mutation in the OBSL1 gene: a 1149C-A transversion in exon 3, resulting in a cys383-to-ter substitution (C383X; 610991.0002), and a 10-bp deletion in exon 3 (610991.0003), respectively.
In a 16-month-old Turkish girl with 3M syndrome, Keskin et al. (2017) identified homozygosity for this mutation, which they designated c.1273dupA, in the OBSL1 gene. Her unaffected consanguineous parents were heterozygous for the mutation. Although Keskin et al. (2017) referred to the effect on the protein in their patient as Thr45AsnfsTer40, and in previously reported patients as Thr245fsTer40, they stated in a personal communication (Keskin, 2019) that Thr425AsnfsTer40 is the correct designation.
For discussion of the cys383-to-ter (C383X) mutation in the OBSL1 gene that was found in compound heterozygous state in a patient with 3M syndrome-2 (3M2; 612921) by Hanson et al. (2009), see 610991.0001.
For discussion of the 10-bp deletion in the OBSL1 gene that was found in compound heterozygous state in a patient with 3M syndrome-2 (3M2; 612921) by Hanson et al. (2009), see 610991.0001.
In a patient with 3M syndrome-2 (3M2; 612921), Hanson et al. (2009) identified a homozygous 1-bp insertion (690insC) in exon 2 of the OBSL1 gene, resulting in a frameshift and premature termination. The mutation affected all OBSL1 isoforms.
In 2 Egyptian brothers with 3M syndrome-2 (3M2; 612921), originally reported by Temtamy et al. (2006), Hanson et al. (2009) identified a homozygous 1463C-T transition in exon 4 of the OBSL1 gene, resulting in an arg489-to-ter (R489X) substitution. The mutation affected all OBSL1 isoforms.
In a 16.5-year-old Turkish boy with 3M syndrome (3M2; 612921), Demir et al. (2013) identified homozygosity for a deletion-insertion mutation (c.457_458delinsT) in exon 2 of the OBSL1 gene, causing a frameshift resulting in gly153fs. His unaffected first-cousin parents were heterozygous for the mutation.
Demir, K., Altincik, A., Bober, E. Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation. J. Pediat. Endocr. Metab. 26: 147-150, 2013. [PubMed: 23457316] [Full Text: https://doi.org/10.1515/jpem-2012-0239]
Geisler, S. B., Robinson, D., Hauringa, M., Raeker, M. O., Borisov, A. B., Westfall, M. V., Russell, M. W. Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to obscurin. Genomics 89: 521-531, 2007. [PubMed: 17289344] [Full Text: https://doi.org/10.1016/j.ygeno.2006.12.004]
Hanson, D., Murray, P. G., Sud, A., Temtamy, S. A., Aglan, M., Superti-Furga, A., Holder, S. E., Urquhart, J., Hilton, E., Manson, F. D. C., Scambler, P., Black, G. C. M., Clayton, P. E. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. Am. J. Hum. Genet. 84: 801-806, 2009. [PubMed: 19481195] [Full Text: https://doi.org/10.1016/j.ajhg.2009.04.021]
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]
Keskin, M., Sahin, N. M., Kurnaz, E., Bayramoglu, E., Erdeve, S. S., Aycan, Z., Cetinkaya, S. A rare cause of short stature: 3M syndrome in a patient with novel mutation in OBSL1 gene. J. Clin. Res. Pediat. Endocr. 9: 91-94, 2017. Note: Erratum: J. Clin. Res. Pediat. Endocr. 11: 109 only, 2019. [PubMed: 27796265] [Full Text: https://doi.org/10.4274/jcrpe.3238]
Keskin, M. Personal Communication. Ankara, Turkey 01/29/2019.
Temtamy, S. A., Aglan, M. S., Ashour, A. M., Ramzy, M. I., Hosny, L. A., Mostafa, M. I. 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin. Dysmorph. 15: 55-64, 2006. [PubMed: 16531729] [Full Text: https://doi.org/10.1097/01.mcd.0000198926.01706.33]