Alternative titles; symbols
HGNC Approved Gene Symbol: LARP7
SNOMEDCT: 770564004;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:112,637,143-112,657,586 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | Alazami syndrome | 615071 | Autosomal recessive | 3 |
He et al. (2008) identified human LARP7, which they called PIP7S. The deduced 582-amino acid protein contains an N-terminal La motif (LAM) (see SSB, 109090), followed by an RNA recognition motif (RRM).
By in situ hybridization on E10.5 whole-mount mouse embryos, Alazami et al. (2012) demonstrated ubiquitous expression of Larp7, with high expression in the brain.
Gross (2018) mapped the LARP7 gene to chromosome 4q25 based on an alignment of the LARP7 sequence (GenBank AF068284) with the genomic sequence (GRCh38).
In HeLa cells, about half of positive transcription factor b (P-TEFb; see 603251) is maintained in a catalytically inactive complex, referred to as the 7SK small nuclear ribonucleoprotein (snRNP), containing the 7SK small nuclear RNA (RN7SK; 606515) and HEXIM1 (607328). By affinity purification and immunoprecipitation of HeLa cell nuclear lysates, He et al. (2008) identified PIP7S as a component of the 7SK snRNP. Nearly all nuclear 7SK was associated with PIP7S, and knockdown of PIP7S with short hairpin RNA (shRNA) reduced the levels of 7SK, indicating that PIP7S is required for 7SK stability. Moreover, knockdown of PIP7S with shRNA prevented formation of the 7SK snRNP and enhanced P-TEFb-dependent expression of a human immunodeficiency virus (HIV)-1 long terminal repeat(LTR)-driven reporter gene. Mutation analysis revealed that interaction of PIP7S with 7SK required the La and RRM motifs of PIP7S and the 3-prime UUU(OH) tail of 7SK, suggesting that PIP7S stabilizes 7SK against degradation by 3-prime exonucleases. Knockdown of PIP7S with shRNA in a normal human mammary epithelial cell line disrupted epithelial differentiation and cell morphology and caused P-TEFb-dependent malignant transformation. He et al. (2008) concluded that PIP7S is required for 7SK stability, formation of the 7SK snRNP, and maintenance of P-TEFb in an inactive state.
By functional characterization in yeast, Hussain et al. (2013) demonstrated that full-length human LARP4 (618657), LARP6 (611300), and LARP7 were not tRNA-mediated suppressors, although their La modules (i.e., the LAM and adjacent RRM) alone possessed suppression activity that was independent of stable pre-tRNA 3-prime end protection. Instead, LARP4, LARP6, and LARP7 were RNA chaperones whose activities were independent of UUU-3-prime-OH binding and were centered around the RRM and sequence immediately downstream of the RRM. The tRNA-mediated suppression activity of the La modules was associated with chaperone activity, as the LAM acted as an accessory structure that helped recruit RNA to the adjacent RRM.
By sequencing the LARP7 gene within the critical region of chromosome 4q identified for Alazami syndrome (ALAZS; 615071), characterized by facial dysmorphism, intellectual disability, and primordial dwarfism, in a consanguineous Saudi family, Alazami et al. (2012) identified a homozygous 7-bp duplication in exon 8 (612026.0001), which fully segregated with the disorder. Western blot analysis revealed complete lack of LARP7 on patient cell lysates, and real-time PCR demonstrated reduced LARP7 expression in patient cells, compared to those of healthy controls, in both lymphoblast and fibroblast tissues, suggesting that total loss of the protein was due to nonsense-mediated decay. Concurrent with this was a profound reduction of the 7SK ncRNA. By introducing a LARP7 expression vector, Alazami et al. (2012) rescued 7SK levels in patient fibroblasts. Conversely, siRNA-mediated knockdown using 2 different oligos directed at LARP7 mRNA resulted in ablation of 7SK levels in healthy fibroblast cells.
In 2 affected members of an Iranian family segregating severe intellectual disability and microcephaly, Najmabadi et al. (2011) had identified an 'apparently disease-causing' mutation in the LARP7 gene (612026.0002). No other clinical information was provided.
In a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome, Ling and Sorrentino (2016) identified compound heterozygous frameshift mutations in the LARP7 gene (612026.0003 and 612026.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
In 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome, Imbert-Bouteille et al. (2019) identified a homozygous frameshift mutation in the LARP7 gene (612026.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In affected members of a consanguineous Saudi family with Alazami syndrome (ALAZS; 615071), Alazami et al. (2012) identified a homozygous 7-bp duplication in exon 8 (1024_1030dupAAGGATA) of the LARP7 gene, predicting a frameshift at codon 344 and subsequent premature termination of the peptide after 9 residues (Thr344LysfsTer9). Western blot analysis revealed complete lack of LARP7 on patient cell lysates, and real-time PCR demonstrated reduced LARP7 expression in patient cells, compared to those of healthy controls, in both lymphoblast and fibroblast tissues, suggesting that total loss of the protein was due to nonsense-mediated decay. The mutation was not found in 188 unrelated Saudi controls, a local database of 194 exomes, or the 1000 Genomes Project database.
In 2 affected members of a consanguineous Iranian family segregating severe intellectual disability and microcephaly, Najmabadi et al. (2011) identified an 'apparently disease-causing' homozygous mutation in the LARP7 gene (Lys276fs). No other clinical information was provided.
In a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome (ALAZS; 615071), Ling and Sorrentino (2016) identified compound heterozygous mutations in the LARP7 gene: a 2-bp duplication (c.213_214dup), resulting in a frameshift (Ser72fs), and a 5-bp deletion (c.651_655del; 612026.0004), resulting in a frameshift (Lys219fs). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the 5-bp deletion (c.651_655del) in the LARP7 gene that was found in compound heterozygous state in a patient with Alazami syndrome (ALAZS; 615071) by Ling and Sorrentino (2016), see 612026.0003.
In 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome (ALAZS; 615071), Imbert-Bouteille et al. (2019) identified a homozygous 2-bp insertion (c.524_525insTT, NM_001267039.1) in exon 7 of the LARP7 gene, resulting in a frameshift (Ala176LeufsTer37). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project, 1000 Genomes Project, or gnomAD databases.
Alazami, A. M., Al-Owain, M., Alzahrani, F., Shuaib, T., Al-Shamrani, H., Al-Falki, Y. H., Al-Qahtani, S. M., Alsheddi, T., Colak, D., Alkuraya, F. S. Loss of function mutation in LARP7, chaperone of 7SK ncRNA, causes a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism. Hum. Mutat. 33: 1429-1434, 2012. [PubMed: 22865833] [Full Text: https://doi.org/10.1002/humu.22175]
Gross, M. B. Personal Communication. Baltimore, Md. 2/5/2018.
He, N., Jahchan, N. S., Hong, E., Li, Q., Bayfield, M. A., Maraia, R. J., Luo, K., Zhou, Q. A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. Molec. Cell 29: 588-599, 2008. [PubMed: 18249148] [Full Text: https://doi.org/10.1016/j.molcel.2008.01.003]
Hussain, R. H., Zawawi, M., Bayfield, M. A. Conservation of RNA chaperone activity of the human La-related proteins 4, 6 and 7. Nucleic Acids Res. 41: 8715-8725, 2013. [PubMed: 23887937] [Full Text: https://doi.org/10.1093/nar/gkt649]
Imbert-Bouteille, M., Mau Them, F. T., Thevenon, J., Guignard, T., Gatinois, V., Riviere, J.-B, Boland, A., Meyer, V., Deleuze, J.-F., Sanchez, E., Apparailly, F., Genevieve, D., Willems, M. LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters. Europ. J. Med. Genet. 62: 161-166, 2019. [PubMed: 30006060] [Full Text: https://doi.org/10.1016/j.ejmg.2018.07.003]
Ling, T. T., Sorrentino, S. Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability. Am. J. Med. Genet. 170A: 217-219, 2016. [PubMed: 26374271] [Full Text: https://doi.org/10.1002/ajmg.a.37396]
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]