Mutations in the TTDN1 Gene Are Associated with a Distinct Trichothiodystrophy Phenotype

Abstract

Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur deficient hair with alternating dark and light “tiger tail” banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. While most TTD patients are photosensitive, patients with TTDN1 mutations were reported to be non-photosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe 5 patients from 4 families with defects in the TTDN1 gene: 4 had no photosensitivity while 1 patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (p=0.009 and p=0.024, respectively), while some characteristic TTD clinical, laboratory, and imaging findings were absent. The 3 oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease.

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

“…In certain instances, the pathological features in TTD are uncoupled from the DNA repair defect. For example, TTD patients carrying mutations in the TTDN1 gene manifest with clinical symptoms associated with the photosensitive TTD disorder but are DNA repair‐proficient and show no signs of photosensitivity or cancer proneness . Recently, it was discovered that a TTD causative TFIIEβ mutation did not affect the GG‐NER or TC‐NER sub‐pathways of NER, uncoupling any defects in transcription from DNA repair in TTD …”

Trichothiodystrophy type 4 in an Indian family

“…MPLKIP encodes for the protein M-phase-specific PLK1-interacting protein (MPLKIP) having 179 amino acid residues. It is ubiquitously expressed in epidermis of the skin, hair follicles, and other organs like brain, heart, liver, kidney, skeletal muscle, pancreas, lung, and placenta (Heller et al, 2015). It plays a role in mitosis and cytokinesis during cell cycle.…”

ERCC2 mutations in two siblings with a severe trichothiodystrophy phenotype

“…The extent of symptoms correlates mainly with the amount of damaged transcription factor and its product. Half of the TTD patients show a photosensitivity without sun‐induced skin cancers, but patients with TTDN1 mutations were reported to be non‐photosensitive . The ERCC2 gene is most commonly involved in TTD, but different mutations in this gene may lead to distinctive phenotypes including xeroderma pigmentosum group D (XPD), Cockayne syndrome‐like phenotypes (CS), cerebro‐oculo‐facio‐skeletal syndrome (COFS) or a complex overlap, illustrating the clinical and genetic heterogeneity of these disorders …”