Molecular characteristics
LARP7 (La Ribonucleoprotein Domain Family, Member 7) gene is located at 4q25 and encodes a protein that complexes with 7SK, an ncRNA, to form 7SK snRNP complex. This complex functions to supress the general transcription factor P-TEFb (positive transcription elongation factor b), thereby hindering RNAP II from elongating transcripts. 7SK also competes with DNA for binding to HMGA1, an architectural transcription factor, and thus directly regulates its activities.
Mutations and pathophysiology
LARP7 serves to protect 7SK from degradation, and mutations in LARP7 have been shown to lead to 7SK depletion and cause the phenotype observed in Alazami syndrome. Depletion of LARP7 has also been shown to cause a reduction in telomerase activity and progressively shortening telomeres. Some examples of pathogenic variants are shown below:
Alazami et al. (2012) reported a homozygous 7bp duplication in exon 8 of LARP7 (c.1024_1030dupAAGGATA) leading to frameshift and premature termination of the protein (p.T344Kfs*9). The affected patients came from a consanguineous Saudi family and displayed the phenotypical features of Alazami syndrome.
Najmabadi et al. (2011) reported a homozygous frameshift mutation in LARP7 (Lys276fs) in two affected individuals from a consanguineous Iranian family.
Ling and Sorrentino (2016) reported a compound heterozygous mutation (c.213_214dup and c.651_655del) leading to a frameshift (Lys219fs). The affected patient was a Caucasian girl born of unrelated parents.
Holohan et al. (2016) identified a homozygous mutation (c.756_757del) leading to frameshift and premature termination of the protein (p.Arg253Ile*6). The affected patient came from a Canadian family and displayed the phenotypical features of Alazami syndrome.
Imbert-Bouteille et al. (2018) recently reported a homozygous frameshift mutation in exon 7 of LARP7 (c.524_525insTT (p.(Ala176Leufs*37)) affecting two sisters from an Algerian consanguineous family.
Dateki et al. (2018) recently reported a novel compound heterozygous mutation involving (c.370delG and c.641_667+25del causing p.Glu124fs*38 and p.Phe192fs*13, respectively) affecting a Japanese patient from a non-consanguineous family.