Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome

Abstract

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

Figure 1

Characteristic Craniofacial and Limb Malformation in Individuals with Nager Syndrome and SF3B4 Mutations Typical features of the face include downslanted palpepral fissures, malar flattening, and variable external ear malformations. Hand abnormalities include small thumbs and, in some cases, upper-limb reduction defects (C-1). Labels correspond to those in Tables 1–3, where a detailed description of each individual is provided.

Figure 2

Location of SF3B4 Mutations that Cause Nager Syndrome (A) Distribution of mutations. Red text indicates an initiator methionine mutation, purple text indicates nonsense mutations, green text indicates a splice mutation, and black text indicates frameshift mutations. (B) Domain structure of SAP49. The following abbreviation is used: RRM, RNA recognition motif. (C) Predicted translational effect of each SF3B4 mutation. Dotted lines indicate a deletion, the blue box indicates reference amino acid sequences, the red bar indicates altered amino acid sequences, and asterisks indicate potential for nonsense-mediated RNA decay.