Dataset Information

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

ABSTRACT: PURPOSE:To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS:Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS:Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION:These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

SUBMITTER: Johnston JJ

PROVIDER: S-EPMC6105555 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Johnston Jennifer J JJ van der Smagt Jasper J JJ Rosenfeld Jill A JA Pagnamenta Alistair T AT Alswaid Abdulrahman A Baker Eva H EH Blair Edward E Borck Guntram G Brinkmann Julia J Craigen William W Dung Vu Chi VC Emrick Lisa L Everman David B DB van Gassen Koen L KL Gulsuner Suleyman S Harr Margaret H MH Jain Mahim M Kuechler Alma A Leppig Kathleen A KA McDonald-McGinn Donna M DM Can Ngoc Thi Bich NTB Peleg Amir A Roeder Elizabeth R ER Rogers R Curtis RC Sagi-Dain Lena L Sapp Julie C JC Schäffer Alejandro A AA Schanze Denny D Stewart Helen H Taylor Jenny C JC Verbeek Nienke E NE Walkiewicz Magdalena A MA Zackai Elaine H EH Zweier Christiane C Zenker Martin M Lee Brendan B Biesecker Leslie G LG

Genetics in medicine : official journal of the American College of Medical Genetics 20180222 10

<h4>Purpose</h4>To characterize the molecular genetics of autosomal recessive Noonan syndrome.<h4>Methods</h4>Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.<h4>Results</h4>Twelve families with a total of ...[more]

PMID: 29469822

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Project description:RationaleNoonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches.ObjectiveBleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders.Methods and resultsWhole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

Dataset Information

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Publications

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

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