Advisory Committee Chair
Ludwine M Messiaen
Advisory Committee Members
Bruce R Korf
Michael R Crowley
Upender Manne
Bradley K Yoder
Document Type
Dissertation
Date of Award
2014
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Schwannomatosis is the third major form of the neurofibromatoses. Constitutional mutations in the SMARCB1 gene have been found only in ~50% of familial and <10% of sporadic schwannomatosis patients, suggesting additional predisposing genes exist. In the present study, we sequenced 3.72 Mb of evolutionary conserved sequences along 22q in 8 schwannomatosis patients without a SMARCB1 mutation in blood or schwannomas, and had a molecular signature consisting of somatic partial loss of 22q and a different NF2 mutation in every schwannoma. We identified LZTR1 germline mutations in 7/8 patients. Targeted sequencing of LZTR1 in 12 further patients with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of the LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ~80% SMARCB1-negative 22q-related schwannomatosis patients. Neurofibromatosis type 1, another major form of neurofibromatoses, is caused by loss-of-function mutations in the NF1 gene. Approximately 2% of identified NF1 mutations are deep intronic splice mutations causing the inclusion of an intronic cryptic exon in the mature mRNA. In the present study, we identified 12 different deep intronic splice mutations in 15 unrelated probands, resulting in exonization of different fragments from intron 30(23.2) or 31(23a). This study describes the largest collection of deep intronic mutations in NF1 reported so far, and pinpoints specifically the intronic sequences flanking the alternatively spliced exon 31(23a) as a hotspot for NF1 intronic splice defects. Further investigation by fragment and cloning analysis uncovered that the deep intronic mutations residing either 5' or 3' of exon 31(23a) predominantly or preferentially affect the type II isoform including exon 31(23a), suggesting that alternative splicing of exon 31(23a) depends and is regulated by multiple flanking intronic sequences.
Recommended Citation
Xie, Jing, "Identification of a new schwannomatosis-predisposing gene and study of splicing defects caused by deep intronic NF1 mutations causing neurofibromatosis type 1" (2014). All ETDs from UAB. 3387.
https://digitalcommons.library.uab.edu/etd-collection/3387