Constructive rescue of TFIIH instability by an alternative isoform of XPD derived from a mutated XPD allele in mild but not severe XP-D/CS

Mutations in xpd cause xeroderma pigmentosum (xp), xp and cockayne syndrome (cs) crossover syndrome (xp/cs), trichothiodystrophy and cerebro-oculo-facio-skeletal syndrome (cofs). cofs represents the most severe end of the cs spectrum. this study reports two japanese patients, cofs-05-135 and cofs-chiba1, who died at ages of <1 year and exhibited typical cofs manifestations caused by xpd mutations p.[i619del];[r666w] and p.[g47r];[i619del], respectively. two other cases of severe xp-d/cs (xp group d/cs), xp1ji (p.[g47r];[0]) and xpcs1pv (p.[r666w];[0]), died at ages <2 years. on the other hand, two cases of mild xp-d/cs, xp1ne (p.[g47r];[l461v;v716_r730del]) and xpcs118lv (p.[l461v;v716_r730del];[r666w]), lived beyond 37 years of age. p.i619del and p.[l461v;v716_r730del] are functionally null; therefore, despite the differences in clinical manifestations, the functional protein in all of these patients was either p.g47r or p.r666w. to resolve the discrepancies in these xpd genotype–phenotype relationships, the p.[l461v;v716_r730del] allele was analyzed and we found that p.[l461v;a717g] was expressed from the same allele as p.[l461v;v716_r730del] by authentic splicing. additionally, p.[l461v;a717g] could partially rescue the loss of xpd function, resulting in the milder manifestations observed in xp1ne and xpcs118lv.