Dominant Noonan syndrome-causing <i>LZTR1</i> mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling

Motta, Marialetizia; Fidan, Miray; Bellacchio, Emanuele; Pantaleoni, Francesca; Schneider-Heieck, Konstantin; Coppola, Simona; Borck, Guntram; Salviati, Leonardo; Zenker, Martin; Cirstea, Ion Cristian; Tartaglia, Marco

doi:10.1093/hmg/ddy412

Cited by 63 publications

(76 citation statements)

References 57 publications

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“…Further studies describing other de novo disease‐causing mutations will help refine the regions implicated in the AD form of NS. A recent structural analysis of LZTR1 indicates that AD‐acting variants typically lie on the top surface of a six‐blade propeller‐like structure . Most de novo variants identified here fit with that pattern, however p.R97L and the familial p.N145I are buried toward the side of the propeller structure; we suspect these may abrogate phosphorylation (Supplementary note 3, http://www.matteoferla.com/LZTR1.html).…”

Section: Discussionsupporting

confidence: 56%

“…A recent structural analysis of LZTR1 indicates that AD-acting variants typically lie on the top surface of a six-blade propeller-like structure. 28 Most de novo variants identified here fit with that pattern, however p.R97L and the familial p.N145I are buried toward the side of the propeller structure; we suspect these may abrogate phosphorylation (Supplementary note 3, www.matteoferla.com/LZTR1.html). In the AR form, compoundheterozygosity often involves a LoF allele in trans with a presumed hypomorphic variant, with mutations typically spread across the gene ( Figure 2D).…”

Section: Clinical Comparison and Face2gene Analysissupporting

confidence: 52%

“…Recent work by Motta et al indicates that missense alterations associated with AR inheritance typically influence protein synthesis/stability or subcellular localization. In contrast, mutations associated with the AD form are expressed normally but enhance EGF‐dependent ERK1/2 phosphorylation . Functional studies such as these are especially important for the missense alterations described here where pathogenicity has not been conclusively established (Table S7, Supplementary note 4).…”

Section: Discussionmentioning

confidence: 97%

“…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%

“…The exception to this rule was O1504902 who harbored missense variants at adjacent codons ( Figure S2). 28 Functional studies such as these are especially important for the missense alterations described here where pathogenicity has not been conclusively established (Table S7, Supplementary note 4). Using a combination of parent-child exomes and allele-specific PCR showed that 5/5 de novo mutations reported here occurred on the paternal chromosome.…”

Section: Clinical Comparison and Face2gene Analysismentioning

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: Discussionsupporting

confidence: 56%

Section: Clinical Comparison and Face2gene Analysissupporting

confidence: 52%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Comparison and Face2gene Analysismentioning

confidence: 99%

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

et al. 2019

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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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Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

Leoni

Blandino

Delogu

et al. 2021

American J of Med Genetics Pt A

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Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype‐ phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single‐center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid‐shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

show abstract

Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling

Cited by 63 publications

References 57 publications

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

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

Providing more evidence on LZTR1 variants in Noonan syndrome patients

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

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