De novo mutations in MLL cause Wiedemann-Steiner syndrome

Abstract

Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.

Figure 1

Clinical Images of Individuals in whom Mutations Were Identified in MLL (A) Slim yet muscular build and the characteristic facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures. A broad nasal bridge, a wide nasal tip, and a Cupid’s bow contour to the upper lip are also seen. (B) Hypertrichosis cubiti—excessive hair growth on the extensor surface of the distal upper arm and proximal forearm (individual WSS-1).

Figure 2

Domain Structure of MLL and the Locations of the Observed Mutations The identified mutations are each predicted to cause premature termination of the protein product before the translation of the C-terminal region containing the FRYC motif, the Win motif, and the SET domain.

Figure 3

Total Abundance of MLL Transcript in Primary Skin Fibroblasts from WSS-3 and the Average of Two Unrelated Healthy Controls MLL expression normalized to endogenous GAPDH and RPLO expression levels. Error bars represent SEM of three independent experiments. UHC, unrelated healthy controls.