A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

Authors:
Karen W Gripp
Karen W Gripp
A. I. duPont Hospital for Children
Wilmington | United States
Kimberly A Aldinger
Kimberly A Aldinger
The University of Chicago
United States
James T Bennett
James T Bennett
Tulane University School of Medicine
United States
Laura Baker
Laura Baker
University of Southern California
United States
Jessica Tusi
Jessica Tusi
A. I. duPont Hospital for Children
Toronto | Canada
Nina Powell-Hamilton
Nina Powell-Hamilton
Brigham and Women's Hospital (JAG); and Harvard Medical School (JAG)
Saudi Arabia
Deborah Stabley
Deborah Stabley
Nemours Biomolecular Core Laboratory
United States
Katia Sol-Church
Katia Sol-Church
United States

Am J Med Genet A 2016 09 5;170(9):2237-47. Epub 2016 Jun 5.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc.

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Source
http://dx.doi.org/10.1002/ajmg.a.37781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134331PMC

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September 2016
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