Submission Details

Primary Ciliary Dyskinesia (PCD) is a motile ciliopathy characterized by respiratory tract infections, body laterality defects and could be associated with infertility. Mutations in PCD patients have been identified in a heterogeneous group of genes normally expressed in cilia and/or sperm flagella (PMID: 33279404).

The AK7 (Adenylate kinase 7) gene was first reported in PCD patients in 2012 (PMID: 22801010), and in association with Spermatogenic failure 27 (MONDO:0054731, OMIM: 617965), in 2018 (PMID: 29365104).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group and due to the differences in molecular mechanism and the phenotypic variability, the ClinGen Motile Ciliopathy GCEP working group estimated that PCD (MONDO: 0016575) and Spermatogenic failure 27 (MONDO:0054731) represent distinct diseases and decided to split the entities. Evidence from four probands (PMID: 22801010 and PMID: 29365104) is included in this curation. However, in three patients, only a heterozygous mutation was detected (PMID: 22801010), and in the fourth patient mild respiratory signs, normal ciliary beating and normal ultrastructure were observed. Therefore, the score of the genetic evidence is downgraded to zero.

AK7 is phosphotransferase that catalyzes the interconversion of nucleoside phosphates. This reaction provides energy for cellular processes requiring a stable supply of ATP, such as ciliary beating. The AK7 protein has a WcaG motif near the N terminus, followed by an AK domain and a C-terminal DPY30 motif. The WcaG motif is a signature of some prokaryotic nucleoside diphosphate sugar epimerases, and the DPY30 is a protein oligomerization motif.

The expression pattern of AK7 is similar to PCD-related genes which are particularly expressed in ciliated epithelia and sperm flagella (PMID: 25613900).

In human nasal epithelial cell culture, Knockdown of* AK7* using siRNA caused a reduced AK7 mRNA and protein levels and a decreased ciliary beat frequency (PMID: 20537283). Ak7 knockout mice (Ak7 -/-) were generated by the insertion of a 4.5 kb transgene in the intron 5 of the AK7 gene (PMID: 18776131). No* Ak7* expression was detected in homozygous transgenic mice.

(Ak7 -/-) mice showed growth retardation, hydrocephalus, and PCD signs, including airway dilatation and thickening of airway walls, and excess of mucus in the paranasal sinuses. Male Ak7 -/- mice were infertile. They lacked mature spermatids and spermatozoa, and electron microscopy showed abnormal sperm heads and absence of tail structures.

Electron microscopy analysis of airway epithelial cells revealed reduced number of motile cilia, and cilia showed axonemes with central complex defect and microtubules disorganization. Using video microscopy, cilia of the airway epithelial cells showed a significantly reduced ciliary beat frequency (PMID: 18776131). Similar results were reported in (PMID: 21746835).

In the patient reported in (PMID: 29365104), the expression of AK7 was only altered in sperm. Compared to control, a normal expression pattern of AK7 was observed in the patient’s airway epithelial cells. This experimental evidence contradicts the association of AK7 with PCD.

In summary, the evidence supporting the relationship between AK7 and autosomal recessive PCD has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role AK7 plays in this disease.This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 9, 2023 (SOP Version 9).