A novel MPLKIP‐variant in three Finnish patients with non‐photosensitive trichothiodystrophy type 4

Abstract

Trichothiodystrophy is a group of multisystem neuroectodermal disorders with dysplastic hair as the cardinal symptom. We describe three patients from two Finnish families in whom whole‐exome sequencing revealed a novel homozygous variant, c.26del, p.(Pro9Glnfs*144) in the MPLKIP‐gene, confirming the diagnosis of non‐photosensitive trichothiodystrophy type 4 (TTD4). The variant was confirmed by Sanger sequencing and inherited from unaffected carrier parents. This report adds to the literature by expanding the genetic and phenotypic spectra of MPLKIP‐related trichothiodystrophy. We describe dysmorphic features in the patients and provide a comparison of clinical characteristics in patients with TTD4 reported to date.

Trichothiodystrophy‐associated MPLKIP maintains DBR1 levels for proper lariat debranching and ectodermal differentiation

“…All individuals carry homozygous, potential deleterious variants in MPLKIP , also known as TTDN1 (Fig 2C ; Table EV1 ), including the novel frameshift NM_138701.4 (MPLKIP):c.61del (p.Trp21GlyfsTer132) in affected siblings TTD289IS and TTD290IS; homozygous nonsense c.85G>T (p.Gly29Ter) in individuals TTD287IS, TTD295IS, and siblings TTD288IS and TTD303IS; and homozygous frameshift NM_138701.4 (MPLKIP):c.505dup (p.Thr169AsnfsTer32) in affected individual TTD299IS. The latter two mutations were previously found to be associated with TTD (Strang‐Karlsson et al , 2021 ). The respective parents were confirmed to be heterozygous for the variants (Fig EV1 ).…”

“…We postulated that the functional decline in for example, gene expression by this remarkable protein frailty would become especially apparent in highly or terminally differentiated cell types, explaining that phenotypes are observed in specific tissue only. It is however excluded that instability of the MPLKIP protein itself underlies TTD‐specific features, since a significant part of MPLKIP ‐mutated patients carry null alleles (e.g., large genomic deletions spanning the entire gene) and consequently will not produce any MPLKIP protein at all (Heller et al , 2015 ; Strang‐Karlsson et al , 2021 ). We therefore wondered if MPLKIP deficiency might reduce steady‐state protein levels of complex partners of MPLKIP, as previously observed with TFIIE and TFIIH associated TTD mutations.…”