Cryptorchidism: Novel genetic insights into CCDC149 mutations

One boy's gene mutation was knocked into mice, who developed undescended testes and poor sperm quality

Journal: Andrology | Published: 2025-06-03 | Type: Journal Article, Case Report, Research Support, Non-U.S. Gov't | PMID: 40459248 Authors: Du Shengrong, Xu Shan, Yang Lei, Ye Yan, Wu Yuhan, Xiao Ziyun, Dong Xiuqing, Yao Wenliang, Li Hua (Fujian Medical University-affiliated labs and hospitals, China) Funding/COI: Funded by Fujian provincial science and technology foundations; authors report no conflicts of interest

Summary

Researchers sequenced the exome of an 8-year-old boy with bilateral cryptorchidism (undescended testes) and found a homozygous nonsense mutation in CCDC149, a gene not previously linked to testicular descent. To test whether the mutation actually causes the condition, they used CRISPR/Cas9 to delete the same gene in mice, and the knockout mice also developed undescended testes plus abnormal sperm (oligoasthenoteratozoospermia — low count, poor motility, abnormal shape).

Claims

• Whole-exome sequencing identified a homozygous nonsense mutation (NM_001395273.1: c.448C>T, p.Gln150Ter) in CCDC149 in a boy with bilateral cryptorchidism
• The boy's parents are second cousins and both heterozygous carriers, consistent with autosomal recessive inheritance
• Ccdc149 knockout mice showed undescended testes and oligoasthenoteratozoospermia
• Single-cell RNA sequencing analysis (performed on public human testis datasets, not the knockout mice themselves) showed altered expression of AMH and several muscle-related genes, which the authors propose as a mechanistic link to testicular descent

Study Quality

This is a case report (n=1 human patient and family) paired with a CRISPR knockout mouse model. The human genetics is solid as far as it goes: a rare, private variant, segregating with disease in a consanguineous family in a pattern consistent with recessive inheritance, confirmed by Sanger sequencing. But one family cannot establish that CCDC149 mutations are a real or recurrent cause of human cryptorchidism — that requires the variant, or others in the same gene, showing up in additional unrelated cases, which the authors explicitly acknowledge is missing.

The mouse data is the paper's strongest piece of evidence: the knockout phenotype (undescended testes, poor sperm quality) mirrors the human presentation, which is a legitimate functional validation that most single-case reports lack. The mechanistic claim is weaker than the results section implies, though — the single-cell RNA sequencing used to link CCDC149 to AMH and muscle-gene expression was run on a public human testis dataset (GSE124263), not on tissue from the actual knockout mice. The authors disclose this gap themselves in their limitations section, but the abstract and discussion blur the distinction, making the "regulatory interaction" sound more directly demonstrated than it is.

Red Flags

• Human evidence is a single family — no replication cohort, so the mutation's causal role in human cryptorchidism remains unconfirmed
• The scRNA-seq "mechanism" data comes from an unrelated public human dataset, not from the Ccdc149 knockout mice — the paper's own limitations section admits this, but the results/discussion present it as if it directly explains the mouse phenotype
• No rescue experiment (restoring wild-type CCDC149 to reverse the mouse phenotype) to strengthen the causal case
• Mouse cohort sizes aren't reported in the material provided

Strengths

• Trio sequencing with Sanger confirmation and a consistent autosomal recessive segregation pattern
• CRISPR knockout mouse model that reproduces the core human phenotype (undescended testes, abnormal sperm)
• No pharma funding or declared conflicts of interest
• Authors transparently flag the study's own limitations (single case, no matched mouse scRNA-seq) rather than glossing over them

Verdict

A genuinely interesting lead — a new candidate gene for cryptorchidism with a knockout mouse model that recapitulates the human phenotype — but it's built on one family, and the mechanistic story linking CCDC149 to AMH and muscle genes leans on a public human dataset rather than data from the actual mutant mice. Worth watching for follow-up studies that test the gene in a larger cryptorchidism cohort; not yet evidence that CCDC149 is a common or established cause of the condition.