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AK2
adenylate kinase 2
AK2 is located on the short (p) arm of chromosome 1, at band 1p35.1. Arm ratio per GRCh38 - banding schematic.
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Overview
AK2 is located on chromosome 1 at position 1p35.1 and encodes a 239-amino-acid enzyme known as adenylate kinase 2. This protein functions primarily in the mitochondrial intermembrane space, where it catalyses the interconversion of adenine nucleotides to help cells maintain appropriate ATP levels. The gene follows an autosomal recessive inheritance pattern, meaning that pathogenic variants in both copies are required to cause disease. Conditions associated with AK2 dysfunction typically manifest in early life and affect tissues with high energy demands, particularly developing immune cells. Understanding AK2 function is important for carrier screening programmes that identify individuals at risk of transmitting severe congenital disorders to their children.
What the gene does
Adenylate kinase 2 catalyses the reversible transfer of phosphate groups between adenine nucleotides, converting two molecules of ADP into one ATP and one AMP. This reaction plays a crucial role in maintaining the balance of adenine nucleotides within mitochondria, particularly in cells undergoing rapid proliferation or differentiation. The enzyme helps ensure that ATP, the cell's primary energy currency, remains available even when mitochondrial oxidative phosphorylation is under stress. By monitoring and adjusting nucleotide ratios, AK2 supports cellular energy sensing and metabolic regulation. This function becomes especially critical in haematopoietic cells during early development, where energy demands are substantial as precursor cells differentiate into mature immune components. Disruption of this enzymatic activity can impair cellular differentiation pathways and compromise the survival of rapidly dividing cell populations.
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Chromosome location
The AK2 gene is located on the short arm of chromosome 1 at cytogenetic band 1p35.1. This chromosomal region contains multiple genes involved in developmental and metabolic processes. The precise genomic coordinates and exon structure contribute to the gene's expression profile across different tissues, with notably high expression in bone marrow and developing lymphoid tissues.
Protein structure
The adenylate kinase 2 protein contains several functionally important regions that enable its catalytic activity. The NMP region, spanning amino acids 45 to 74, is involved in nucleotide binding and substrate recognition. The LID region, extending from amino acids 141 to 178, undergoes conformational changes during the catalytic cycle, facilitating substrate positioning and product release. Within the LID region, a disordered segment from amino acids 150 to 169 provides structural flexibility that may be important for the enzyme's dynamic function. These domains work together to enable the efficient transfer of phosphate groups between adenine nucleotides in the mitochondrial intermembrane space.
Key variants
Pathogenic variants in AK2 are predominantly loss-of-function changes that reduce or eliminate enzyme activity. Most disease-causing variants are missense substitutions that disrupt the protein's catalytic efficiency or stability, though nonsense and frameshift variants have also been reported. The severity of clinical presentation can vary depending on the residual enzyme activity retained by specific variant combinations, with complete loss of function generally associated with the most severe phenotypes.
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.307C>T | p.Arg103Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency disease |
c.330+5G>A | - | Pathogenic | ★★☆☆ | Reticular dysgenesis |
c.498+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency disease |
c.545C>A | p.Ala182Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Reticular dysgenesis |
g.(?_33473829)_(33478866_?)del | - | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
g.(?_33480103)_(33480215_?)del | - | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
g.(?_33490023)_(33502429_?)del | - | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
c.374_375del | p.Val125fs | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
c.409C>T | p.Arg137Ter | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
c.597_599dup | p.Tyr200Ter | Pathogenic | ★☆☆☆ | Reticular dysgenesis |
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 AK2 cause reticular dysgenesis, the most severe form of severe combined immunodeficiency. Affected infants present shortly after birth with profound lymphopenia, absence of functional neutrophils, and sensorineural hearing loss. The condition results from impaired energy metabolism in haematopoietic precursors, preventing normal differentiation of immune cells. Without haematopoietic stem cell transplantation in the neonatal period, reticular dysgenesis is typically fatal due to overwhelming infection. The rarity of this condition means that most carriers of AK2 variants are identified through cascade testing following a diagnosis in a family member or through expanded carrier screening programmes.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic AK2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
AK2 appears on several NHS Genomic Medicine Service gene panels, reflecting its clinical importance in rare disease diagnosis. The gene holds green (diagnostic-grade) status on the Cytopenia panel (excluding Fanconi anaemia), the Primary Immunodeficiency or Monogenic Inflammatory Bowel Disease panel, and the Developmental Disorders Genotype-to-Phenotype database (DDG2P). It also appears on the COVID-19 research panel. These panel memberships support the use of AK2 sequencing in NHS laboratories when investigating severe early-onset immunodeficiency, unexplained cytopenia in infancy, or complex developmental presentations with immune dysfunction.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of an AK2 variant?
Carriers have one working copy and one non-working copy of the AK2 gene. Carriers do not develop reticular dysgenesis themselves but can pass the variant to their children. If both parents are carriers, each pregnancy has a 25% chance of being affected.
How common are AK2 variants in the population?
AK2-related reticular dysgenesis is extremely rare, with fewer than 100 cases reported worldwide. Carrier frequency varies by population but is generally very low, though specific founder variants may be more common in isolated communities.
Can AK2 variants be detected through standard newborn screening?
Standard UK newborn screening does not specifically test for AK2 variants. However, severe combined immunodeficiency screening programmes in some regions may identify affected infants through lymphocyte markers, prompting genetic investigation that can reveal AK2 pathogenic variants.