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. 2012 Feb 10;90(2):369-77.
doi: 10.1016/j.ajhg.2011.12.023. Epub 2012 Feb 2.

Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly

Matthew A Lines  1 , Lijia Huang, Jeremy Schwartzentruber, Stuart L Douglas, Danielle C Lynch, Chandree Beaulieu, Maria Leine Guion-Almeida, Roseli Maria Zechi-Ceide, Blanca Gener, Gabriele Gillessen-Kaesbach, Caroline Nava, Geneviève Baujat, Denise Horn, Usha Kini, Almuth Caliebe, Yasemin Alanay, Gulen Eda Utine, Dorit Lev, Jürgen Kohlhase, Arthur W Grix, Dietmar R Lohmann, Ute Hehr, Detlef Böhm; FORGE Canada Consortium; Jacek Majewski, Dennis E Bulman, Dagmar Wieczorek, Kym M Boycott
Collaborators, Affiliations

Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly

Matthew A Lines et al. Am J Hum Genet. .

Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.

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Figures

Figure 1
Figure 1
Characteristic Craniofacial Dysmorphism in MFDM The detailed clinical description of these individuals is reported in Table 1. Typical findings include a sloping forehead, malar hypoplasia, micrognathia, a wide mouth, and a characteristic external ear appearance (preauricular tags, microtia, a small superior helix, and a prominent lobe with a square posterior margin). Microtia is variable in severity; some patients have a cupped ear configuration. (A) Individual 11: birth (B) Individual 11: 19 months (C) Individual 8: 8 months (D) Individual 8: 24 months (E) Individual 12: 7 years (F) Individual 3: 6 years, 5 months (G) Individual 2: 3.5 years (left) and 10.5 years (right) (H) Individual 9: 13 years, 5 months (I) Individual 4: 16 years, 8 months
Figure 2
Figure 2
Locations of Disease-Causing Mutations in EFTUD2 (A) Intron-exon structure of EFTUD2 (introns not to scale) with the locations of ten MFDM-causing point mutations (relative to NM_004247.3). Missense mutations are shown in blue, truncating (nonsense and frameshift) mutations are shown in red, and the intron 16 splice-donor mutation is shown in green. (B) Domain architecture of U5-116kDa (after Fabrizio et al., 1997) indicates the locations of point mutations (the color scheme is the same as that in A). (C) Exome-sequencing read depth in proband 1 shows a zone of reduced coverage (dashed box) extending from exons 20–29 of EFTUD2 into the adjoining gene (HIGD1B). A corresponding microdeletion was confirmed by microarray (coordinates are listed in Table 3).
Figure 3
Figure 3
Predicted Structural Effects of MFDM-Causing Missense Mutations We modeled residues 114–957 of EFTUD2 on the crystal structure of S. cerevisiae ribosomal elongation factor 2 (eEF2) by using ModWeb, and we visualized them in PyMol. (A) Crystal structure of eEF2 (PDB: 1N0U) complexed with the translation inhibitor sordarin (yellow). Structural domains are highlighted. (B) U5-116kD model based on eEF2. The modeled portion of U5-116kD has high identity (37%) with eEF2; ModWeb scores this model as “reliable” (GA341 score is 1.00). (C) Locations of amino acid substitutions p.Arg262Trp, p.Cys476Arg, and p.Leu637Arg. (D) Arg262 (red) is predicted to occupy surface of GTP binding site. Also highlighted are additional surface-facing residues of G1 (green), G4 (yellow), and G5 (orange) motifs. (E) Arg262Trp alteration in individual 2 is predicted to alter GTP-binding surface topology. (F) Leu637 sidechain (helix II of domain III) is predicted to face inward and to form close hydrophobic contacts with Ile590 and Ile629. Leu637Arg (individual 11) is predicted to introduce a positive charge at this location. (G) Cys476 is situated at the center of domain II's β barrel structure. p.Cys476Arg (individual 12) is predicted to introduce a positive charge at this position. (H) Multispecies alignments of U5-116kDa illustrate sequence conservation in the vicinity of missense mutations identified in individuals with MFDM.
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