Spermatogenic Failure 47 (SPGF47): DZIP1-related asthenoteratozoospermia with MMAF

Scope of this report. I ran a few targeted searches and read one primary paper in full (Lv et al. 2020). The disease rests on essentially one published study, so most template sections are marked "not available". I cite PMIDs only where I confirmed them. Other claims are cited by URL. Treat the mechanism of DZIP1 in sperm as partly inferred from non-sperm systems.

1. Disease information

SPGF47 is an autosomal recessive form of male infertility caused by biallelic loss-of-function or missense variants in DZIP1 (DAZ interacting zinc finger protein 1, 13q32.1). Affected men have asthenoteratozoospermia with severe multiple morphological abnormalities of the sperm flagella (MMAF). Their sperm are immotile, and most lack flagella.

• Identifiers: MONDO:0030844 (as given). OMIM 619102 per MGI's disease page and search results. Gene OMIM 608671. Orphanet, ICD-10 and MeSH were not checked.
• Synonyms: SPGF47; DZIP1-related MMAF; DZIP1-related asthenoteratozoospermia.
• Data source: The disease-level description comes from one case report of two individuals. Gene-disease evidence is described as limited (Molecular Interaction Atlas curation label, per search results; this is not an explicit OMIM statement).
• Unrelated association at the same locus: OMIM lists a questionable autosomal dominant entry, mitral valve prolapse 3 (610840), for DZIP1. It is a separate phenotype and should not be merged with SPGF47.

2. Etiology

• Causal factor: Genetic. Homozygous DZIP1 variants were found in two men from consanguineous families (PMID:32051257).
• Risk and protective factors: No environmental, lifestyle, modifier or protective factors have been reported. Heterozygous carriers (the parents of one proband) were not reported as affected, and heterozygous knockout mice were fertile like wild type.
• Gene-environment interactions: None reported.

3. Phenotypes

Source for all rows below: PMID:32051257 (n = 2, ages 27 and 28).

• Severity and onset: Severe, with a presumed congenital basis. The ages at which infertility was recognised were not reported.
• Frequency: In the MMAF cohort of 65 unrelated Han Chinese men, 2 carried DZIP1 variants (3.1%).
• Other findings: Normal 46,XY karyotype, no large Y-chromosome deletions, and no other ciliopathy signs were found in the two men. Semen volume was normal. I did not check whether the paper reports hormone levels or testis volume.
• Quality of life: Not reported.

4. Genetic and molecular information

• Gene: DZIP1 (hgnc: not verified here; look it up before binding). It has zinc-finger and coiled-coil domains.
• Variants (PMID:32051257):
• c.188G>A, p.Arg63Gln. This is a homozygous missense variant at a conserved residue, predicted deleterious by SIFT, PolyPhen-2 and MutationTaster.
• c.690T>G, p.Tyr230*. This is a homozygous stop-gain, with both parents heterozygous. It lies at the start of the first coiled-coil domain, so all three coiled-coil domains are lost.
• Neither variant appears in 1000 Genomes, ExAC or gnomAD, or in Han Chinese controls.
• The paper's Methods give the stop-gain as p.Tyr23* while the Results and Figure 1 give p.Tyr230*. Curators should record the discrepancy and use p.Tyr230*.
• Origin and function: Germline. The variants are described as loss of function. Per the paper, the variant constructs in HEK293T cells gave reduced or truncated protein.
• ClinVar and ClinGen classification: Not checked.
• Modifier, epigenetic and chromosomal data: None reported.

5. Environmental information

None reported. There are no known toxin, lifestyle or infectious contributors.

6. Mechanism and pathophysiology

Causal chain (steps 1–4 are demonstrated in patients or knockout mice; step 5 is inferred from other systems):

1. Biallelic DZIP1 variants (p.Arg63Gln, or truncation at Tyr230) lead to loss of DZIP1 protein. Patient sperm showed absent DZIP1 signal.
2. DZIP1 loss results in abnormal centrioles in sperm (abnormal centrin1 dot counts, in about half or more of sperm in one proband).
3. Abnormal centrioles lead to weak, misplaced or absent IFT88 and IFT140 signals. This is correlative in patient sperm.
4. Failed axoneme assembly results in absent or short flagella (MMAF) and immotile sperm, hence asthenoteratozoospermia and male infertility. Knockout mice reproduce this endpoint with infertile males, few and immotile sperm, and mostly absent flagella.

5. Inferred: In other systems DZIP1 acts at the basal body and centriolar satellites. It forms a BBSome–DZIP1–PCM1 complex and promotes ciliary Rab8 activation via GDI2 (GSK3β–Dzip1–Rab8 study). A Drosophila study reports a role for Dzip1 in basal body docking during spermatogenesis (per search summary). The Lv et al. discussion cites these ideas. This work did not test whether those same steps are the mechanism in human sperm.

6. Suggested GO terms (verify before use): cilium assembly (GO:0060271), sperm flagellum assembly or axoneme assembly, and centriolar satellite as a cellular component.

7. Cell types: spermatid (CL:0000018) and spermatozoon (CL:0000019). DZIP1 is expressed mainly in testis, especially elongating spermatids in mouse.
8. Omics, immune and metabolic changes: None reported.

7. Anatomical structures affected

• Organs: testis and epididymis, with a reproductive-system phenotype only in the reported patients.
• Cells and subcellular: elongating spermatids; the sperm centriole/basal body and the flagellar axoneme. In human sperm DZIP1 localizes to the head and neck.
• Laterality: Not applicable. Findings are in semen.
• Suggested UBERON: testis (UBERON:0000473) and epididymis (UBERON:0001301).

8. Temporal development

Presumed congenital. Infertility becomes apparent in adulthood on semen analysis. No data exist on progression, remission or critical periods.

9. Inheritance and population

• Inheritance: Autosomal recessive (HP:0000007). Both families were consanguineous.
• Population: Both families were Han Chinese. Founder effects, carrier frequency, prevalence and geographic variant distribution are unknown.
• Sex: Affected phenotype is male. Whether female carriers have any phenotype was not reported.
• Penetrance and expressivity: Not established, since only two individuals are reported.

10. Diagnostics

• Semen analysis: Low motility with a high proportion of absent or short flagella.
• Electron microscopy: Absent or very short axonemes.
• Immunofluorescence: Absent DZIP1 and weak or misplaced IFT88 and IFT140 in sperm. This is a research method.
• Genetic testing: Exome sequencing found both variants. A reasonable approach is to include DZIP1 on MMAF or male infertility gene panels. The paper does not give formal testing recommendations.
• Differential diagnosis: Other MMAF genes. The paper names DNAH1, CEP135, CATSPER2 and SUN5 as related asthenoteratospermia genes (search summary), and known genes explain only about half of cases. Primary ciliary dyskinesia should also be considered, although the two probands had no other ciliopathy features.

11. Outcome and prognosis

No survival, life-expectancy or quality-of-life data. The phenotype appears limited to infertility, with no systemic complications reported in the two men.

12. Treatment

• ICSI or other assisted reproduction outcomes: Not reported in the paper. The authors say the probands will be followed up.
• Other therapies: No gene therapy, drug or clinical trial was identified (no search of ClinicalTrials.gov was run).
• Reasoning only: Because nearly all sperm lack flagella and are immotile, outcomes of assisted reproduction cannot be predicted from the available data.

13. Prevention

Genetic counselling for consanguineous couples. Recurrence risk is 25% per pregnancy when both parents are carriers, which follows from autosomal recessive inheritance. No screening programs or environmental measures apply.

14. Other species and natural disease

No naturally occurring disease in other species was identified (OMIA was not searched).

15. Model organisms

• Mouse knockout (PMID:32051257): CRISPR-Cas9 frameshift allele c.102_132del (p.Ala35Serfs*13), with DZIP1 protein absent.
• All homozygous males were infertile.
• Very few epididymal sperm were recovered, none motile.
• Most sperm were severely malformed, mainly with absent flagella, plus cytoplasmic residue and abnormal heads.
• Heterozygous males did not differ from wild type.
• The mouse study did not directly assess centrioles or IFT.
• The mouse phenotype closely matches the human MMAF phenotype.
• Other systems: Zebrafish (iguana) and mouse embryonic fibroblasts support a role in ciliogenesis (GSK3β–Dzip1–Rab8; also an unreviewed Hedgehog-signalling paper at pure.psu.edu). A Drosophila study reports a role in basal body docking in spermatogenesis. I did not verify these models independently.
• Limitations: Mouse centriole and IFT phenotypes were not tested, and the human data come from two individuals.

Gaps and cautions for curators

• Single report. All patient-level evidence comes from PMID:32051257. I did not find a second family or case series.
• Unverified identifiers. I did not verify HGNC, GO, CL, UBERON or HPO CURIEs. Look each one up before binding.
• Quotes. I read the paper through a summarising tool and did not extract exact abstract quotes. Fetch the cached reference with just fetch-reference PMID:32051257 and copy snippets from it.
• Unread part of the paper. The last ~2,500 characters of the PMC page were not read.

Sources

• Lv et al. 2020, J Med Genet 57:445–453, PMID:32051257 (PMC7361034)
• J Med Genet article page
• MGI disease page, OMIM:619102
• GlyCosmos entry for SPGF47
• GSK3β–Dzip1–Rab8 cascade and ciliogenesis
• Dzip1 and Hedgehog signalling

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• HP:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility
• UBERON:0000473 (1 mention) - the report calls it "Suggested UBERON: testis"; UBERON calls it testis**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0000798 (1 mention) - the report calls it "Oligospermia"; HP calls it Oligozoospermia, and lists "Oligospermia" among its other names
• CL:0000018 (1 mention) - the report calls it "Cell types: spermatid"; CL calls it spermatid**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.