p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

Abstract

Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.

Figure 1

The c.5425C>T change in NF1 is associated with a distinctive NF1 form. (a) Pedigrees of the three families cosegregting NF1 and the NF1 mutation. Squares and circles indicate males and females, respectively; open symbols indicate unaffected individuals, filled symbols indicate affected individuals; arrows indicate index cases, and symbols with a slash indicate deceased family members. WT, wild-type allele. (b) Representative clinical features of subjects heterozygous for the c.5425C>T missense change in NF1. This mutation is associated with a mild phenotype consisting mainly of pigmentary signs (CaLS and SF) and lack of NFs. Other typical findings, including LN, OPGs and osseous dysplasia are uncommon or absent, whereas a high incidence of facial features resembling NS is observed. (c) Location of Arg¹⁸⁰⁹ in the tridimensional structure of the neurofibromin Sec/PH-like bipartite module. The cartoon shows the ribbon representation of the module together with location of the residue (lateral chain reported as stick representation) mutated in the studied NF1 subjects. The Sec domain (residues 1560–1698) (pink), which is implicated in lipid binding, is connected to a regulatory PH-like domain (residues 1715–1816) (light blue) by a partly helical linker (residues 1699–1714) (yellow). Arg¹⁸⁰⁹ (red) is in close contact with the backbone of Ser¹⁷³⁸ (dark blue). The H-bond between these residues is also shown (black line).