Submission Details

Spermatogenic failure-27 (SPGF27) is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are short, absent, irregularly shaped, and coiled. Ultrastructural analysis shows loss of the central pair of microtubules, loss of the inner dynein arms, and peripheral doublet disorganization (PMID: 29365104). The AK7 (Adenylate kinase 7) gene was first reported in association with Spermatogenic failure 27 (MONDO:0054731, OMIM: 617965) in 2018 (PMID: 29365104), and in PCD patients in 2012 (PMID: 22801010). 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 Spermatogenic failure 27 (MONDO:0054731), and in PCD patients in 2012 (PMID: 22801010) represent distinct diseases and decided to split the entities. Evidence from two probands (PMID: 29365104 and PMID: 34854019) is included in this curation. Homozygous missense mutations were detected in both patients. Less than half a point (0.4) is reached with this genetic evidence. AK7 is phosphotransferase that catalyzes the interconversion of nucleoside phosphates. This reaction provides energy for cellular processes requiring a stable supply of ATP. 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.
This gene-disease association is supported by experimental evidence. Abundant data confirms the expression of AK7 in sperm flagella (PMID: 25613900, PMID: 29365104). Moreover, in patients with AK7 mutations, the expression of the protein in sperm was altered (PMID: 29365104 and PMID: 34854019). 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, 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 (PMID: 18776131). Similar results were reported in (PMID: 21746835 and PMID: 29365104). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 9, 2023 (SOP Version 9).