Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype

Abstract

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.

Many roads lead to oncogene-induced senescence

“…Consistent with the hypothesis that Sprouty may also function to attenuate the effects of NF1 mutations, Sprouty has been shown to be downregulated in human malignancies associated with NF1 as compared to cognate premalignant lesions (neurofibromas) (Holtkamp et al, 2004). Moreover, the Sprouty-related gene SPRED 1 has recently been reported to be genetically inactivated in a syndrome with features similar to NF1 (Brems et al, 2007). Sprouty genes have also been shown to be suppressed in breast, prostate and lung cancer (reviewed in Lo et al, 2006), providing circumstantial evidence that Sprouty proteins could play a broader role in tumor suppression.…”

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

“…Their phenotype included café-au-lait spots, freckling, learning disabilities, and development delay (Supplementary Table S4), as previously reported. 21,22,33,34 Because of the important clinical overlap with NF1, it is impossible to diagnose the syndrome exclusively based on clinical feature alone. In patients presenting solely with café-au-lait spots and/or frecklings, a molecular confirmation has to be performed.…”

“…Individuals with NF1 generally require routine clinical management to detect and manage the manifestations. On the basis of the current understanding of Legius syndrome, affected individuals are not at increased risk for the typical NF1-associated tumours, 21,22,33,34 and generally do not require the same intensity of clinical management. A diagnosis of Legius syndrome compared with NF1 may provide both peace of mind due to decreased risk of a tumour phenotype and cost savings for the individual due to less aggressive medical management.…”

“…20 Genetic heterogeneity has been found in NF1 by identification of a novel disorder, the Legius syndrome, caused by mutations in the SPRED1 gene. [21][22][23] SPRED1 encodes a negative regulator of the RAS-MAPK pathway. It is located on 15q13.2 and spans 104.4 kb of genomic sequence.…”

Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

“…Spreds bind to Ras and Raf, thereby suppressing activation of Raf. It is clear that Spred1 is involved in the suppression of the Ras-ERK pathway in vivo, as a loss-of-function mutation of SPRED1 gene was found in human NCFC syndrome, which is caused by dysregulation of the RTK/Ras/ERK pathway (Brems et al, 2007). On the other hand, several mechanisms for the Sprouty-mediated inhibition of the RTK/Ras/ERK pathway have been proposed, including the avoidance of Grb2-Sos recruitment (Gross et al, 2001;Hanafusa et al, 2002) or the inhibition of Raf Sasaki et al, 2003).…”