KLHL25

Chr 15

kelch like family member 25

ENSG00000183655 UniProt: Q9H0H3 OMIM: 619893

KLHL25 encodes a substrate-specific adapter protein that functions within the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex to regulate protein translation homeostasis and lipid metabolism through targeted degradation of EIF4EBP1 and ACLY proteins. Pathogenic variants cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, involving the central nervous system with seizures and developmental delays typically manifesting in early infancy. The gene shows tolerance to loss-of-function variation in the general population, suggesting that biallelic variants are required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex involved in various processes, such as translation homeostasis and lipid synthesis (PubMed:22578813, PubMed:27664236, PubMed:34491895). The BCR(KLHL25) ubiquitin ligase complex acts by mediating ubiquitination of hypophosphorylated EIF4EBP1 (4E-BP1): ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) probably serves as a homeostatic mechanism to maintain translation and prevent eIF4E inhibition when eIF4E levels are low (PubMed:22578813). The BCR(KLHL25) complex does not target EIF4EBP1 (4E-BP1) when it is hyperphosphorylated or associated with eIF4E (PubMed:22578813). The BCR(KLHL25) complex also acts as a regulator of lipid synthesis by mediating ubiquitination and degradation of ACLY, thereby inhibiting lipid synthesis (PubMed:27664236, PubMed:34491895). BCR(KLHL25)-mediated degradation of ACLY promotes fatty acid oxidation and is required for differentiation of inducible regulatory T (iTreg) cells (PubMed:34491895)

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

1.92

LOEUF

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Mechanism

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.92LOEUF

pLI 0.000

Z-score -1.61

OE 1.49 (1.02–1.92)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.43Z-score

OE missense 1.20 (1.11–1.30)

478 obs / 397.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.49 (1.02–1.92)

0≤0.351.4

Missense OE?1.20 (1.11–1.30)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 19 / 12.8Missense obs/exp: 478 / 397.8Syn Z: -1.63

Background carrier burden — how many people carry a rare variant somewhere in KLHL25?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

1,027 rare PASS variants

Rare truncating (LoF)

1 in 800

159 rare PASS variants

Rare synonymous (reference)

1 in 84

421 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL25. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 61	1 in 800
South Asian	~43k	1 in 38	1 in 700
Remaining (unassigned)	~30k	1 in 55	1 in 570
European (Finnish)	~27k	1 in 280	1 in 4,300
Admixed American	~22k	1 in 65	1 in 1,600
African / African American	~21k	1 in 48	1 in 680
East Asian	~20k	1 in 44	1 in 560
Ashkenazi Jewish	~13k	1 in 89	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 49	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓