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Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

ABSTRACT: Constitutional SMARCB1 mutations at 22q11.23 have been found in ?50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ?80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.

SUBMITTER: Piotrowski A

PROVIDER: S-EPMC4352302 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

Piotrowski Arkadiusz A Xie Jing J Liu Ying F YF Poplawski Andrzej B AB Gomes Alicia R AR Madanecki Piotr P Fu Chuanhua C Crowley Michael R MR Crossman David K DK Armstrong Linlea L Babovic-Vuksanovic Dusica D Bergner Amanda A Blakeley Jaishri O JO Blumenthal Andrea L AL Daniels Molly S MS Feit Howard H Gardner Kathy K Hurst Stephanie S Kobelka Christine C Lee Chung C Nagy Rebecca R Rauen Katherine A KA Slopis John M JM Suwannarat Pim P Westman Judith A JA Zanko Andrea A Korf Bruce R BR Messiaen Ludwine M LM

Nature genetics 20131222 2

Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identifie ...[more]

PMID: 24362817

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Project description:Background & aimsNon-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway.MethodsPatients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/-) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation.ResultsPatients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/- mice exposed to a high-fat diet.ConclusionsOur results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous buildup (scar tissue) and inflammation of the liver tissue. For the first time patients with holoprosencephaly, a disease caused by SHH signaling mutations, are shown to have increased liver steatosis independent of obesity. This observation was recapitulated in a mouse model of attenuated SHH signaling that also showed increased liver steatosis but with decreased fibrosis and inflammation. While SHH inhibition is associated with a good NAFLD prognosis, this increase in liver fat accumulation in the context of SHH signaling inhibition must be studied prospectively to evaluate its long-term effects, especially in individuals with Western-type dietary habits.

Dataset Information

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

Publications

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

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