Mosaic RASopathies

Hafner, Christian; Groesser, Leopold

doi:10.4161/cc.23108

Cited by 87 publications

(101 citation statements)

References 72 publications

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“…In an analogy to a group of phenotypically overlapping developmental syndromes caused by germline mutations in components of the Ras-Raf-MEK-ERK signaling pathway that have been designated as ''RASopathies'' (Tidyman and Rauen, 2009), the term ''mosaic RASopathies'' has been suggested for congenital disorders that are caused by mosaic mutations of the same pathway (Hafner and Groesser, 2013). Our findings in patients with PPK incorporate this syndrome to the group of mosaic RASopathies.…”

Section: Discussionmentioning

confidence: 59%

Phacomatosis Pigmentokeratotica Is Caused by a Postzygotic HRAS Mutation in a Multipotent Progenitor Cell

Groesser

Herschberger

Sagrera

et al. 2013

Journal of Investigative Dermatology

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116

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Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.

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Section: Discussionmentioning

confidence: 59%

Phacomatosis Pigmentokeratotica Is Caused by a Postzygotic HRAS Mutation in a Multipotent Progenitor Cell

Groesser

Herschberger

Sagrera

et al. 2013

Journal of Investigative Dermatology

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116

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“…This phenomenon can be explained by assuming that early during embryogenesis a melanocyte precursor cell acquires a somatic NRAS mutation, which gives rise to a mosaic pattern of NRASmutated cells that further migrate and colonize the skin and/or leptomeninges. This pathogenetic mechanism fits the spectrum of mosaic RASopathies that is characterized by post-zygotic mutations resulting in the presence of two genetically distinct cell populations in the same organism (51). The exact timing of acquisition of the NRAS mutation during embryogenesis (and thus the position of the migrating precursor cell at that time) might influence the eventual phenotype ( Figure 5).…”

Section: Nras Mutations In Pediatric Lmns and Ncmmentioning

confidence: 94%

Primary Melanocytic Tumors of the Central Nervous System: a Review with Focus on Molecular Aspects

Küsters‐Vandevelde

Küsters

Grunsven³

et al. 2015

Brain Pathology

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Primary melanocytic tumors of the central nervous system (CNS) represent a spectrum of rare tumors. They can be benign or malignant and occur in adults as well as in children, the latter often in the context of neurocutaneous melanosis. Until recently, the genetic alterations in these tumors were largely unknown. This is in contrast with cutaneous and uveal melanomas, which are known to harbor distinct oncogenic mutations that can be used as targets for treatment with small-molecule inhibitors in the advanced setting. Recently, novel insights in the molecular alterations underlying primary melanocytic tumors of the CNS were obtained, including different oncogenic mutations in tumors in adult patients (especially GNAQ, GNA11) vs. children (especially NRAS). In this review, the focus is on molecular characteristics of primary melanocytic tumors of the CNS. We summarize what is known about their genetic alterations and discuss implications for pathogenesis and differential diagnosis with other pigmented tumors in or around the CNS. Finally, new therapeutic options with targeted therapy are discussed.

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“…For instance, the same genetic alteration in genes in the RAS–MAPK pathway can result in very diverse phenotypes, depending on the timing at which they arise [164, 170, 171]. Mutations in HRAS mutating codon G12 of the HRAS protein have been identified in Costello syndrome when present in the germline [172], but postzygotic and embryonic occurrences of mutations in this residue have been observed in Schimmelpenning syndrome [164], sebaceous nevus [164], keratinocytic epidermal nevi [173], and early-onset bladder cancer [157, 174].…”

Section: De Novo Mutations In Human Diseasementioning

confidence: 99%

New insights into the generation and role of de novo mutations in health and disease

2016

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Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent–offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

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Mosaic RASopathies

Cited by 87 publications

References 72 publications

Phacomatosis Pigmentokeratotica Is Caused by a Postzygotic HRAS Mutation in a Multipotent Progenitor Cell

Phacomatosis Pigmentokeratotica Is Caused by a Postzygotic HRAS Mutation in a Multipotent Progenitor Cell

Primary Melanocytic Tumors of the Central Nervous System: a Review with Focus on Molecular Aspects

New insights into the generation and role of de novo mutations in health and disease

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