Curation HSAN-VIII PRDM12

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.