All ETDs from UAB

Advisory Committee Chair

Ludwine M Messiaen

Advisory Committee Members

Stephen L Carroll

Robert A Kesterson

Bruce R Korf

Upender Manne

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neurofibromatosis Type 1, a common autosomal dominant disorder with neuro-cardio- facio-cutaneous presentation, is caused by mutations in the NF1 gene, a negative regulator of RAS-MAPK signaling. The presentation of NF1 is overlapping, yet clinically distinct from other diseases of RAS-MAPK signaling. An RNA-based comprehensive approach for mutation detection identifies an NF1 alteration in over 95% of non-founder NF1 patients with a classical NF1 presentation. However, no NF1 mutation was identified in 54.2% of the 2432 patients referred for molecular diagnostics due to the presence one or more NF1 related sign between August 2003 and July 2007. In order to clarify the etiology of the phenotype of those patients in whom no NF1 mutation was identified, other negative regulators of RAS-MAPK signaling were explored including SPRED1, the gene recently associated with Legius syndrome. Copy number analysis for the SPRED1 gene and mutation screening of members of the SPRED and SPRY gene families were performed. Four deletions and 36 minor lesion SPRED1 mutations were found in 510 NF1 mutation negative individuals referred for SPRED1 clinical molecular testing. One SPRY1 nonsense mutation (c.100C>T, p.Gln34*) and two SPRY2 deletions (c.282_345del, p.His96Glyfs*20 and c.474_488del, p.Gly161_Pro165del) were identified along with several missense alterations with unknown significance. No common phenotype was observed in non-related individuals with a SPRY1 or SPRY2 missense or likely loss of function alteration. These results indicate that SPRED1 deletions may account for 10% of the mutations observed in patients and copy number analysis should be included in SPRED1 molecular diagnostics but that SPRY1 and SPRY2 mutations do not appear to be a common cause of disease in this cohort of patients.

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