Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1–PPP1CB complexes

Umeki, Ikumi; Niihori, Tetsuya; Abe, Taiki; Kanno, Shin Ichiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Nagasaki, Keisuke; Yoshida, Makoto; Ohashi, Hirofumi; Inoue, Shin–Ichi; Matsubara, Yoichi; Fujiwara, Ikuma; Kure, Shigeo; Aoki, Yoko

doi:10.1007/s00439-018-1951-7

Cited by 67 publications

(78 citation statements)

References 30 publications

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“…Combining our results with those described in the literature, 9,15,20,27 hypertrophic cardiomyopathy was reported in 5/26 of individuals with AD-acting mutations but 19/26 of those harbouring biallelic variants (Tables S2 and S6). A systematic analysis of cardiac involvement in larger clinical cohorts of patients with LZTR1 mutations is warranted to confirm whether this bias is reproducible.…”

Section: Clinical Comparison and Face2gene Analysissupporting

confidence: 84%

“…Here, the de novo configuration was less certain (pp_dnm = 0.93) but later confirmed by Sanger sequencing of patient/parental DNA. Unlike the other de novo variants identified, p.G248R was reported in gnomAD as a singleton (Table ) and in two independent NS families . Patient 278971's most significant clinical issues relate to perinatal asphyxia.…”

Section: Resultsmentioning

confidence: 89%

“…These disorders all result from dysregulation of RAS‐MAPK signalling so have collectively been termed the “RASopathies”. LZTR1 has only recently been functionally linked to RAS‐MAPK signalling, which explains why its role in NS long went unrecognised. For instance, the gene was absent from a list of 789 RAS–ERK pathway genes prioritised by Chen et al such that the pathogenicity of p.R237Q/p.A249P identified in that study was only realised subsequently .…”

Section: Discussionmentioning

confidence: 99%

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Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐ associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB , consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities ( P = 0.0005), supporting a causal role for LZTR1 . Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

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Section: Clinical Comparison and Face2gene Analysissupporting

confidence: 84%

Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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“…Matsubara, 2016). Recently, recessive variants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) were identified from genetic analyses of NS patients who had tested negative for known RAS/MAPK gene mutations (Johnston et al, 2018;Nakaguma, Jorge, & Arnhold, 2019;Umeki et al, 2018). LZTR1 is now emerging as a novel causative gene of NS pathophysiology.…”

Section: Of 6 |mentioning

confidence: 99%

“…Eighty percent of the patients carry dominant mutations in either the PTPN11 , KRAS , SOS1 , SOS2 , RAF1 , NRAS , BRAF , or RIT1 , all of which are members of the RAS/MAPK signaling cascade (Aoki, Niihori, Inoue, & Matsubara, ). Recently, recessive variants in the LZTR1 ( leucine‐zipper‐like transcription regulator 1 ) gene (OMIM #600574) were identified from genetic analyses of NS patients who had tested negative for known RAS/MAPK gene mutations (Johnston et al, ; Nakaguma, Jorge, & Arnhold, ; Umeki et al, ). LZTR1 is now emerging as a novel causative gene of NS pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish

Nakagama

Takeda

Ogawa

et al. 2019

Molec Gen & Gen Med

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Background Variants in the LZTR1 (leucine‐zipper‐like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking. Methods By CRISPR‐Cas9 genome editing, we generated lztr1‐mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome. Results A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss‐of‐function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome‐associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue. Conclusion Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss‐of‐function mechanism of disease‐causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow‐up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.

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Providing more evidence on LZTR1 variants in Noonan syndrome patients

Chinton

Huckstadt

Mucciolo

et al. 2019

American J of Med Genetics Pt A

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Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain‐of‐function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients.

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Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1–PPP1CB complexes

Cited by 67 publications

References 30 publications

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish

Providing more evidence on LZTR1 variants in Noonan syndrome patients

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