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DIAPH1
diaphanous related formin 1
The DIAPH1 gene provides instructions for making the diaphanous related formin 1 protein, a key regulator of the actin cytoskeleton involved in cell shape, migration, and other cellular functions. DIAPH1 plays a crucial role in forming and maintaining the actin cytoskeleton, a dynamic network essential for many cellular processes.
DIAPH1 is located on the long (q) arm of chromosome 5, at band 5q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DIAPH1 gene, known as diaphanous related formin 1, is essential for regulating the actin cytoskeleton, a fundamental component of cell structure and movement. The protein produced from this gene helps in processes such as cell division, migration, and the formation of specialised cellular structures.
Dysregulation of DIAPH1 function can therefore have widespread effects, impacting various tissues and organs. Understanding DIAPH1's role can shed light on the mechanisms behind inherited conditions where these processes are impaired.
What the gene does
The protein encoded by DIAPH1 is a member of the formin family, which are central organisers of the actin cytoskeleton. Its primary function involves nucleating and elongating unbranched actin filaments, which are crucial for maintaining cell shape, polarity, and movement. DIAPH1 interacts with other proteins to regulate these processes, acting as a molecular scaffold that coordinates different cellular pathways.
Specifically, DIAPH1 is involved in processes like cytokinesis (cell division), cell adhesion, and vesicle trafficking. It also plays a role in signal transduction pathways that translate external cues into changes in cell architecture and behaviour. The protein's ability to precisely control actin dynamics is vital for the development and proper functioning of many physiological systems, including the nervous system and blood cells.
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Chromosome location
The DIAPH1 gene is situated on chromosome 5, specifically at position 5q31.3. This location indicates its physical address within the human genome. Genes at this chromosomal band have been implicated in various biological processes.
Protein structure
The DIAPH1 protein is composed of 1272 amino acids and features several distinct domains critical for its function. It begins with a Disordered region (amino acids 1-84), followed by a GBD/FH3 Domain (amino acids 84-449), which is involved in autoinhibition and interaction with Rho GTPases. A Coiled coil region (amino acids 468-572) is present, along with another Disordered region (amino acids 573-755).
Further along the protein are an FH1 Domain (amino acids 583-764), characterised by polyproline stretches, and an FH2 Domain (amino acids 769-1171), which is responsible for actin nucleation and elongation. Another Coiled coil (amino acids 1039-1196) and a DAD Domain (amino acids 1194-1222) complete the protein structure, where the DAD domain is crucial for intramolecular regulation.
Key variants
Variations within the DIAPH1 gene can alter the function of the diaphanous related formin 1 protein. These genetic changes can manifest as different types of variants, including substitutions, deletions, or insertions, which may affect protein production or the protein's ability to interact with other molecules or regulate actin dynamics. The clinical impact of a specific DIAPH1 variant often depends on its location within the gene and how it affects protein structure and function.
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.1051C>T | p.Arg351Ter | Pathogenic | ★★☆☆ | Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome |
c.2108dup | p.Pro704fs | Pathogenic | ★★☆☆ | Autosomal dominant nonsyndromic hearing loss 1 |
c.2332C>T | p.Gln778Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome |
c.2540_2541del | p.Lys847fs | Pathogenic | ★★☆☆ | Autosomal dominant nonsyndromic hearing loss 1 |
c.3145C>T | p.Arg1049Ter | Pathogenic | ★★☆☆ | Deafness |
c.3268dup | p.Met1090fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant nonsyndromic hearing loss 1 |
c.3637C>T | p.Arg1213Ter | Pathogenic | ★★☆☆ | Rare genetic deafness |
c.991C>T | p.Arg331Ter | Pathogenic | ★★☆☆ | Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome |
c.1609del | p.Leu537fs | Pathogenic | ★☆☆☆ | Autosomal dominant nonsyndromic hearing loss 1 |
c.3516del | p.Glu1173fs | Pathogenic | ★☆☆☆ | Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome |
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
Changes in the DIAPH1 gene are associated with a spectrum of inherited conditions, often exhibiting an autosomal dominant (AD) inheritance pattern. These conditions can affect diverse bodily systems due to the DIAPH1 protein's fundamental role in cellular processes. The specific clinical presentation often depends on the nature and location of the genetic variant.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DIAPH1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
DIAPH1 is recognised in the UK's NHS Genomic Medicine Service, being listed on several Genome England PanelApp panels. These include panels for Bleeding and platelet disorders (R90), Early onset or syndromic epilepsy (R59), Foetal anomalies (R21), Inherited bleeding disorders, Intellectual disability (R29), Monogenic hearing loss (R67), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), and Severe microcephaly (R88). This indicates the gene's significance in diagnosing and managing a variety of inherited conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the DIAPH1 gene?
The DIAPH1 gene provides instructions for making the diaphanous related formin 1 protein, which is crucial for regulating the actin cytoskeleton. This protein helps control cell shape, movement, division, and communication by organising actin filaments.
How can variants in DIAPH1 affect health?
Variants in DIAPH1 can lead to alterations in the protein's function, potentially disrupting cellular processes that rely on proper actin cytoskeleton regulation. This can result in various inherited conditions affecting different body systems, often with an autosomal dominant inheritance pattern.
Is DIAPH1 relevant to NHS genetic testing?
Yes, the DIAPH1 gene is included in several NHS England Genome PanelApp panels, such as those for bleeding and platelet disorders, early onset epilepsy, intellectual disability, and primary immunodeficiency. This highlights its importance in the diagnosis of specific inherited conditions within the UK healthcare system.