A recurrent PDGFRB mutation causes familial infantile myofibromatosis

Abstract

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

Figure 1

Pedigrees of the Four Families with Infantile Myofibromatosis Black filled symbols represent affected family members carrying the PDGFRB c.1681C>T (p.Arg561Cys) mutation. The c.1681C>T variant in individuals II-1 and II-2 in family 1 was identified by WES, and the same mutation in individual III-1 in family 2 was discovered by RNA-seq.

Figure 2

PDGFR-β Substitutions in Familial Infantile Myofibromatosis (A) Domain structure of PDGFR-β and position of identified mutations. Abbreviations are as follows: SP, signal peptide; Ig, immunoglobulin-like C2 domain; TM, transmembrane domain; JM, juxtamembrane domain; KD1, first split kinase domain; KI, kinase insert; KD2, second split kinase domain; CT, C-terminal tail domain. (B) Amino acid conservation across species for the mutated residues. (C) A ribbon diagram showing the interaction between Arg561 and Glu644 in the PDGFR-β model. The backbone of the model is shown in green, with residues of the JM domain colored light green. The p.Arg561Cys substitution would abrogate this interaction. (D) A ribbon diagram showing the interaction between Asn666 and His661 in the PDGFR-β model (green). The structure of the autoinhibited (yellow) and active (purple) forms of KIT kinase are shown for comparison. A p.Asn666Lys change would abolish the interaction linking Asn666 and His661.