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LARP7
La ribonucleoprotein 7, transcriptional regulator
LARP7 is located on the long (q) arm of chromosome 4, at band 4q25. Arm ratio per GRCh38 - banding schematic.
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Overview
LARP7 encodes a member of the La-related protein family, which binds to small nuclear RNAs and regulates their stability and function. The encoded protein plays a critical role in controlling RNA polymerase II, the enzyme responsible for transcribing most protein-coding genes in human cells. Through its interaction with the 7SK small nuclear ribonucleoprotein complex, LARP7 helps coordinate the release of RNA polymerase II from a paused state, enabling efficient gene expression.
Pathogenic changes in LARP7 cause Alazami syndrome, a rare autosomal recessive condition first described in consanguineous Saudi Arabian families. Affected individuals typically present with severe intellectual disability, microcephaly, facial dysmorphism, and skeletal abnormalities. The gene's inclusion on multiple NHS Genomic Medicine Service panels reflects its clinical importance in diagnosing developmental disorders.
What the gene does
The LARP7 protein functions as a key regulator of transcriptional elongation by RNA polymerase II. It binds to 7SK small nuclear RNA, forming a ribonucleoprotein complex that sequesters positive transcription elongation factor b (P-TEFb). This sequestration creates a regulatory checkpoint that prevents premature or uncontrolled transcription.
When cellular conditions require active transcription, P-TEFb is released from the 7SK complex and can then phosphorylate RNA polymerase II, allowing it to transition from transcriptional pausing to productive elongation. LARP7 stabilises the 7SK RNA scaffold that makes this regulatory mechanism possible, protecting the RNA from degradation and ensuring proper assembly of the inhibitory complex.
The protein's RNA-binding capacity depends on its La-type motif and RNA recognition motif domains, which together create a high-affinity binding surface for specific sequences in 7SK RNA. This molecular interaction is essential for normal development, particularly in tissues with high transcriptional demands such as the developing brain.
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Chromosome location
LARP7 is located on the long arm of chromosome 4 at position 4q25. The gene spans approximately 50 kilobases of genomic DNA and contains multiple exons that encode the 582-amino-acid protein. This chromosomal region has been associated with developmental phenotypes in deletion mapping studies, though LARP7 variants themselves cause phenotypes through loss-of-function mechanisms rather than copy number changes.
Protein structure
The LARP7 protein comprises 582 amino acids organised into several functional regions. The N-terminal portion contains an HTH La-type RNA-binding domain (amino acids 28-122) that provides initial recognition of target RNAs. This is followed by an RRM domain (amino acids 125-203) that contributes additional binding specificity and affinity.
The central region of the protein includes extensive disordered segments (amino acids 188-368 and 410-442) that likely provide flexibility for protein-protein interactions and complex assembly. The C-terminal region features an xRRM domain (amino acids 450-563), an atypical RNA recognition motif that may contribute to binding selectivity or protein stability. Small disordered regions at the extreme N-terminus (amino acids 1-27) may serve regulatory functions or facilitate post-translational modifications.
Key variants
Pathogenic variants in LARP7 follow an autosomal recessive inheritance pattern, meaning affected individuals typically carry variants on both copies of the gene. Most reported disease-causing changes are loss-of-function variants, including nonsense mutations that introduce premature stop codons and frameshift variants resulting from small insertions or deletions. These variants disrupt the protein's ability to bind and stabilise 7SK RNA, impairing transcriptional regulation throughout development.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.119dup | p.Gln41fs | Pathogenic/Likely pathogenic | ★★☆☆ | Microcephalic primordial dwarfism, Alazami type |
c.1669-1_1671del | - | Pathogenic | ★★☆☆ | Microcephalic primordial dwarfism, Alazami type |
c.225_226del | p.Ser76fs | Pathogenic | ★★☆☆ | Microcephalic primordial dwarfism, Alazami type |
c.377_378del | p.Thr126fs | Pathogenic | ★★☆☆ | not provided |
c.64_65del | p.Glu22fs | Pathogenic | ★★☆☆ | Microcephalic primordial dwarfism, Alazami type |
c.1491del | p.Phe497fs | Pathogenic | ★☆☆☆ | not provided |
c.259_269del | p.Gly87fs | Pathogenic | ★☆☆☆ | not provided |
c.268dup | p.Ile90fs | Pathogenic | ★☆☆☆ | not provided |
c.66del | p.Val23fs | Pathogenic | ★☆☆☆ | not provided |
c.9_10del | p.Glu4fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in LARP7 cause Alazami syndrome (also known as Alazami-Basit syndrome), a severe neurodevelopmental disorder. Affected individuals present in infancy with profound intellectual disability, absent or severely delayed speech, and marked microcephaly. Additional features typically include distinctive facial characteristics such as a prominent forehead and deep-set eyes, along with skeletal abnormalities affecting the hands and feet.
The phenotypic severity reflects LARP7's essential role in regulating gene expression during critical periods of brain development. Without functional LARP7 protein, cells cannot properly control RNA polymerase II activity, leading to widespread transcriptional dysregulation that particularly affects neuronal differentiation and brain growth.
No disease links recorded for this gene in our reference set.
UK clinical status
LARP7 appears on several NHS Genomic Medicine Service gene panels with green classification, indicating strong evidence for clinical validity. The gene is included on the DDG2P panel for developmental disorders, the Fetal anomalies panel (R21), the Intellectual disability panel (R29), and the Severe microcephaly panel (R88). This multi-panel presence reflects the gene's role in overlapping clinical presentations involving neurodevelopmental delay and structural brain abnormalities. Healthcare providers may consider LARP7 testing when evaluating patients with unexplained microcephaly and severe developmental delay, particularly in families with consanguinity.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is LARP7 and what does it do?
LARP7 encodes a ribonucleoprotein that regulates RNA polymerase II, the enzyme responsible for transcribing most genes. The protein stabilises 7SK RNA, forming a complex that controls when genes are actively transcribed, which is particularly important during brain development.
How are LARP7 variants inherited?
LARP7-related conditions follow an autosomal recessive inheritance pattern. An affected individual typically inherits one pathogenic variant from each parent, both of whom are usually unaffected carriers. Each child of two carrier parents has a 25% chance of being affected.
Why is LARP7 on NHS gene panels?
LARP7 appears on multiple NHS Genomic Medicine Service panels because pathogenic variants cause a recognisable pattern of severe intellectual disability, microcephaly, and developmental anomalies. The gene's inclusion enables earlier diagnosis and supports clinical management for affected families.