Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3

Abstract

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

Figure 1

Phenotypic Characteristics of Individuals with DA8 Five individuals affected by DA8; all individuals shown have MYH3 mutations. Note the downslanting palpebral fissures, ptosis, camptodactyly of the fingers, scoliosis, short stature, and neck webbing. ID numbers for the individuals shown in this figure correspond to those in Table 1, where there is a detailed description of the phenotype of each affected individual. Figure S1 provides a pedigree of each DA8-affected family.

Figure 2

Radiograph of Severe Scoliosis and Vertebral Fusion Observed in a Person with DA8 Severe, convex rightward, rotatory scoliosis of the thoracic and lumbar spine in individual AIII-2 (Table 1 and Figure 1). Fusion of vertebral bodies from T10 to L3 is indicated by the arrow.

Figure 3

Genomic Model of MYH3 and Stylized Structure of Embryonic Myosin Illustrate the Spectrum of Mutations that Cause DA Syndromes MYH3 is composed of 41 exons, 39 of which are protein coding (blue) and two of which are non-coding (orange). (A) Lines with attached dots indicate the approximate locations of MYH3 mutations that cause DA1 (green), DA2A (purple), DA2B (orange), and DA8 (red). The color of each dot reflects the diagnosis. (B) Schematic of an embryonic myosin dimer. The approximate locations of MYH3 mutations relative to each affected amino acid residue in the myosin domain are indicated by colored circles. All mutations causing DA1, DA2A, and DA2B affect amino acid residues located in the motor and neck of embryonic myosin, whereas the two mutations causing DA8 are the only mutations that alter amino acid residues located in the tail. (Both variants in the tail of MYH3 [c.4934A>C (p.Asp1622Ala) and c.2979C>T (p.Ala1637Val)] and reported by Toydemir et al. are now thought to be polymorphisms on the basis of additional family information and frequencies in large databases of control populations.)

Figure 4

Expression of MYH3 in Bone and Cartilage (A) RNA was isolated from a 17-week-old fetus, and cDNA was generated according to standard protocols.MYH3 primers were predicted to yield 313-bp amplicons from genomic DNA (control) and 206-bp amplicons from cDNA. MYH3 cDNA expression was detected in the bone, thymus, placenta, heart, brain, and liver. Expression was not detected in cartilage, lungs, or kidneys. (B) qPCR was used for assessing the relative expression levels of MYH3 cDNA in bone, cartilage, brain, heart, liver, and lungs. MYH3 cDNA expression was detected in bone at a level similar to that observed in the brain and heart and was barely detectable in the lungs and cartilage.