PDILT

Chr 16

protein disulfide isomerase like, testis expressed

Also known as: PDIA7

NCBI Gene: 204474 ENSG00000169340 UniProt: Q8N807 OMIM: 618588

The protein is a redox-inactive chaperone specifically expressed in the testis that is involved in spermatogenesis and belongs to the protein disulfide isomerase family in the endoplasmic reticulum. Mutations cause autosomal recessive male infertility due to multiple morphological abnormalities of the flagella (MMAF), a condition affecting sperm motility and structure. This gene shows very low constraint against loss-of-function variants in the general population, which is consistent with its specialized reproductive function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has has an N-terminal ER-signal sequence, two thioredoxin (TRX) domains with non-classical Ser-Lys-Gln-Ser and Ser-Lys-Lys-Cys motifs, respectively, two TRX-like domains, and a C-terminal ER-retention sequence. The protein lacks oxidoreductase activity in vitro and probably functions as a chaperone. This gene's expression appears to be limited to the testis. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— PDILT

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.000

Z-score 2.30

OE 0.50 (0.32–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.40Z-score

OE missense 1.06 (0.97–1.16)

342 obs / 322.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.50 (0.32–0.80)

0≤0.351.4

Missense OE?1.06 (0.97–1.16)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 12 / 24.2Missense obs/exp: 342 / 322.0Syn Z: -1.21

This gene — mechanism propensity

0.73top 25%

GOF

0.76top 25%

LOF

0.1598th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.