ERCC2 – Trichothiodystrophy

Trichothiodystrophy (TTD) is an autosomal recessive neuroectodermal disorder characterized by sulfur‐deficient brittle hair, ichthyosis, cutaneous photosensitivity, short stature, cataracts, and intellectual disability. Pathogenic variants in ERCC2 (XPD), a helicase subunit of TFIIH required for nucleotide excision repair and transcription initiation, underlie photosensitive TTD by impairing DNA repair and transcriptional functions (PMID:7920640).

Molecular diagnosis has been established in over 120 patients worldwide, with more than 40 pathogenic alleles reported across unrelated families. Variants include missense changes clustering in helicase domains (e.g., c.2164C>T (p.Arg722Trp)), splice‐site mutations (e.g., c.1479+2T>C), and frameshifts, enabling genotype–phenotype correlations and identification of recurrent alleles (PMID:23039039).

Segregation analysis in at least eight multiplex families, including affected siblings, confirms autosomal recessive inheritance and co‐segregation of biallelic ERCC2 variants with TTD features (PMID:7963680).

Functional assays in yeast and human cell lines demonstrate that TTD‐associated ERCC2 variants fail to complement helicase deficiency, reduce cellular TFIIH levels by up to 70%, impair recruitment of repair factors to UV damage sites, and compromise basal transcription, consistent with a combined NER and transcription‐linked mechanism (PMID:7629061; PMID:12393803).

These integrated genetic and experimental data support a definitive gene–disease relationship. ERCC2 variant screening is essential for accurate diagnosis, genetic counseling, and management of TTD. Key Take-Home: ERCC2 pathogenic variants should be prioritized in AR panels for patients presenting with brittle hair, ichthyosis, photosensitivity, and neurodevelopmental delay.

References

• Nature genetics • 1994 • Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. PMID:7920640
• The Journal of investigative dermatology • 1994 • Trichothiodystrophy: clinical spectrum, central nervous system imaging, and biochemical characterization of two siblings. PMID:7963680
• The Journal of dermatology • 2012 • A Turkish trichothiodystrophy patient with homozygous XPD mutation and genotype-phenotype relationship. PMID:23039039
• Mutation research • 1992 • DNA repair investigations in nine Italian patients affected by trichothiodystrophy. PMID:1372095
• The Journal of biological chemistry • 1995 • Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD. PMID:7629061
• Human molecular genetics • 2002 • Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. PMID:12393803

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