Hypopigmentation along Blaschko’s lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.
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The data that support the findings of this study are available from the corresponding authors upon reasonable request.
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We thank the participants and families involved in the study. We also thank the University of Burgundy Centre de Calcul (https://haydn2005.u-bourgogne.fr/dsi-ccub/) for technical support and management of the informatics platform. This work was funded by the Agence Nationale de la Recherche (grant no. ANR-13-PDOC-0029 to J.-B.R.), the Programme Hospitalier de Recherche Clinique National 2010 (grant no. NCT01950975 to P.V.), the NIH (grant no. HD067244 to M.E.R.) and the Société Française de Dermatologie. G.B. has received a Research Scholar Junior 1 (2012–2016) salary award from the Fonds de Recherche du Québec en Santé and the New Investigator salary award (2017–2022) from the Canadian Institute for Health Research (no. MOP-G-287547, file no. 24805).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
a, Craniofacial appearance of affected individuals showing hemifacial microsomia in all subjects. b, Patchy alopecia of hair and beard. c, Teeth anomalies consisting of oligodontia, microdontia, and conical teeth. d, Variable degrees of acral anomalies including symmetric or asymmetric brachydactyly, syndactyly, and polydactyly. Photograph of subject S3 was taken after surgery. e, Linear hypopigmentation following Blaschko’s lines on trunk, limbs, and face. See Supplementary Table 1 for additional details. We obtained written consent to publish photographs of these individuals.
Brain magnetic resonance imaging (MRI) for subjects S1 (at 15 years and 3 months (first row) and six months later (second row)), S2 (third row), and S4 (fourth row). MRI revealed bilateral and symmetrical marked and diffuse hyperintensities on FLAIR images, with sparing of the subcortical white matter/U-fibers. White matter signal abnormalities extend to the anterior limb of the internal capsule, with sparing of the posterior limb of the capsule, associated with either cystic formation (S1) or relative dilatation of the Virchow-Robin spaces (S1, S2, and S4). Note that the corpus callosum is spared. No significant anomalies of thalami and infratentorial cerebellar matter were noted in patients S2 and S4. A posterior fossa cyst is observed in 2 out of 3 patients (S2 and S4), with minimal mass effect on the cerebellum. One focal lesion of the cerebellar white matter was noticed in S1, with a hyperintensity on T2 weighted images. Lesions were stable on the 6-months follow-up MRI for subject S1. It is of interest to note that a leukoencephalopathy with enlarged Virchow-Robin spaces has been described in patients with mutations of PTEN (Vanderver, A. et al. Am. J. Med. Genet. A. 164A, 627–633 (2014)), a gene that encodes an inhibitor of the PI3K-AKT-mTOR signaling pathway and is known to be regulated by RHOA (Li, Z. et al. Nat. Cell Biol. 7, 399–404 (2005)).
Integrative Gemomics Viewer (IGV) screenshots of the de novo postzygotic RHOA c.139G>A substitution (encoding p.(Glu47Lys)) in subject S1 and her parents.
IGV screenshots of the de novo postzygotic RHOA c.139G>A substitution (encoding p.(Glu47Lys)) in subject S2 and his parents.
IGV screenshots of the de novo postzygotic RHOA c.211C>T substitution (encoding p.(Pro71Ser)) in subject S3 and her parents.
IGV screenshots of the NC_012920.1:m.11778G>A, MT-ND4 c.1019G>A, p.(R340H) substitution in S2 (left) and his mother (right).
Supplementary Fig. 7 Expression levels of overexpressed wild-type or mutant myc-tagged RhoA, and endogenous RhoA, total MYPT1, phospho-MYPT1 (pThr696), total MLC2, actin, and phospho-MLC2 (pThr19).
a, Representative Western blots show similar protein loading (endogenous total MYPT1, actin, endogenous RhoA, and total MLC2) and similar overexpression of myc-tagged wild-type and mutant RhoA (three independent experiments). There is a visible reduction in phosphorylated MYPT1(pThr696) and MLC2(pThr19) when RhoA(Thr19Asn) or RhoA(Glu47Lys) are overexpressed. b,c, Levels of phosphorylated MYPT1(pThr696) and MLC2(pThr19) in endogenous and transfected NIH/3T3 cells. Cumulative data of average density values (overlaid with dots from the three independent experiments) for phosphorylated MLC2(pThr19) (b) and MYPT1(pThr696) (c) normalized to total MLC2 and MYPT1, respectively, indicate reduction in MLC2(pThr19) and MYPT1(pThr696) upon RhoA(Thr19Asn) or RhoA(Glu47Lys) overexpression.