HSAN-VIII_PRDM12
- Gene
- PRDM12
- Disease
- HSAN-VIII
- Inheritance
- AR
- Classification
- Moderate
- Total Score
- 11
- Publications Reviewed
- 1
- Publication Span
- Last Updated
- 08/14/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt, Elbay Aliyev
Description
Homozygous PRDM12 polyalanine repeat expansions were reported in two unrelated families with autosomal recessive congenital insensitivity to pain / HSAN-VIII. The TR-specific genetic evidence includes a 19-alanine expansion in family A and an 18-alanine expansion in family J, both exceeding the maximum 14-alanine tract observed in the tested general population. Experimental evidence supports PRDM12 function in nociceptor development and epigenetic regulation, including DRG/nociceptor expression, patient sensory fiber loss, polyalanine-mutant aggregation in transfected cells, and Xenopus sensory placode defects after Prdm12 knockdown. The relationship is currently Moderate, based on one publication without independent replication over time.
Genetic evidence
Total: 5
| Singular Evidence | Probands | PMID:26005867 | 2.5 | Two unrelated families carried homozygous PRDM12 polyalanine expansions. Family A had five affected individuals (P1–P5) with expansion from 12 to 19 alanines, identified after autozygosity mapping and PRDM12 sequencing. Family J had two affected individuals (P17–P18) with a homozygous 18-alanine repeat expansion and a milder CIP/HSAN phenotype. Total TR-specific evidence: 7 affected individuals from 2 unrelated families. |
| Collective Evidence | Computational | PMID:26005867 | 1 | PRDM12 polyalanine tract length was polymorphic in 176 general-population individuals but did not exceed 14 alanines, whereas affected families carried 18- and 19-alanine alleles. The authors considered these expansions exceptional and likely deleterious based on rarity and comparison with other pathogenic polyalanine expansion disorders. |
| Collective Evidence | Segregation | PMID:26005867 | 1.5 | Segregation evidence overlaps with proband evidence for the same two TR-specific families. The paper reports recessive segregation of PRDM12 mutations across all 11 families and asymptomatic heterozygous carriers, but the TR-specific segregation evidence is based on the same families already counted under Probands. |
Experimental evidence
Total: 6
| Function | Biochemical function | PMID:26005867 | 0.5 | PRDM12 is a PRDM-family transcriptional/epigenetic regulator with a PR/SET-related domain, zinc fingers, and a C-terminal polyalanine tract. Wild-type Prdm12 induced H3K9 dimethylation, supporting a biochemical role in histone modification during sensory neurogenesis. |
| Function | Protein interaction | PMID:26005867 | 0.5 | Gene-level evidence: PRDM12 recruits the histone methyltransferase G9a/EHMT2 to mediate H3K9 dimethylation, and the p.His289Leu mutant significantly reduced Prdm12-G9a interaction. This protein-interaction evidence is PRDM12 gene-level and not specific to the polyalanine repeat expansion. |
| Function | Regulatory impact | PMID:26005867 | 1 | Human cell/tissue evidence showed PRDM12 induction during iPSC- and hESC-derived nociceptor-like neuron differentiation and detection in adult human dorsal root ganglia. CIP-associated PRDM12 mutants impaired H3K9 dimethylation, supporting altered epigenetic regulatory function relevant to nociceptor development. |
| Functional Alteration | Patient cells | PMID:26005867 | 1 | Patient tissue studies showed sensory neuron pathology: sural nerve biopsies from affected individuals showed severe loss of small-caliber myelinated Aδ fibers, and skin biopsies showed absent intraepidermal nerve fiber crossing with markedly reduced CGRP-positive nociceptive fibers. |
| Functional Alteration | Non-patient cells | PMID:26005867 | 0.5 | In transfected COS-7 and HEK-293T cells, PRDM12 polyalanine expansion mutants showed reduced protein levels and nuclear/cytoplasmic aggregation; expression was recovered after proteasome inhibition with MG132. |
| Models | Non-human model organism | PMID:26005867 | 2 | Xenopus Prdm12 knockdown caused abnormal expression of cranial sensory placode markers Ath3, Ebf3, and Islet1, supporting a conserved role for Prdm12 in sensory neurogenesis. Mouse embryo studies showed Prdm12 expression in neural folds and dorsal root ganglia during sensory neuron development. |
| Models | Cell culture | PMID:26005867 | 1 | Human iPSC- and hESC-derived nociceptor-like neuron differentiation models showed strong PRDM12 induction during neural crest/sensory neuron specification; mature cells showed nociceptor-associated marker expression and tetrodotoxin-resistant sodium currents. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.