Case report: Identification and clinical phenotypic analysis of novel mutation of the PPP1CB gene in NSLH2 syndrome

Abstract

ObjectiveTo screen and analyze the genetic mutations in the PPP1CB gene in a patient with Noonan syndrome with loose anagen hair-2 (NSLH2) in Yunnan Province, China and explore the possible molecular pathogenesis.MethodsAfter obtaining informed consent, we collected the patient's medical history and carried out physical and laboratory examinations for the NSLH2 proband and the family members. Genomic DNA was extracted from the peripheral blood of all individuals. The coding regions including all pathogenic exons, parts of introns, and promoters of genes were sequenced by next-generation sequencing. Pathogenic mutations, which were detected in the probands and their parents, were verified by Sanger sequencing.ResultsThe clinical manifestations of NSLH2 included prominent forehead, yellowish hair, slightly wide eye distance, sparse eyebrows, bilateral auricle deformity, reduced muscle tension, and cardiac and visual abnormalities. The proband carried a c.371A>G mutation in exon 3 of PPP1CB, which is a missense mutation. This was a de novo mutation as the parents of the proband showed no mutation at this site.ConclusionIn this study, we identified a novel mutation of PPP1CB, which enriched the mutation spectrum of the PPP1CB gene and provided a basis for the diagnosis of NSLH2.

Structural insights into the role of SHOC2‐MRAS‐PP1C complex in RAF activation

“…However, several other NS mutations, such as G53R, M173I/V, Q269R, T411A and two double mutations M173I_L174F and Q269H_H270Y are observed in SHOC2 [37,38,46]. Currently, all seven NS mutations observed in PP1C are only seen in the PP1CB isoform of PP1C [43][44][45][55][56][57]. Two of these seven, P49R and E183A (PP1CB numbering), are present at the PP1C-SHOC2 interface.…”

“…PP1C has previously been noted to prefer small residues and disfavour acidic residues at the +1 position [62]. Four NS mutations have been identified in or around the active site channels of PP1CB; H124R, R220C, D252Y, and E274K [55][56][57]. As these mutations are more than ~20…”

“…PP1C has previously been noted to prefer small residues and disfavour acidic residues at the +1 position [62]. Four NS mutations have been identified in or around the active site channels of PP1CB; H124R, R220C, D252Y, and E274K [55–57]. As these mutations are more than ~20 Å away from any of the protein–protein interfaces, it is possible that these NS mutations affect RAF substrate binding or catalytic activity of PP1C rather than SMP complex assembly.…”