The historical Coffin–Lowry syndrome family revisited: Identification of two novel mutations of RPS6KA3 in three male patients

Abstract

Coffin-Lowry syndrome (CLS) is a rare X-linked dominant disorder characterized by intellectual disability, craniofacial abnormalities, short stature, tapering fingers, hypotonia, and skeletal malformations. CLS is caused by mutations in the Ribosomal Protein S6 Kinase, 90 kDa, Polypeptide 3 (RPS6KA3) gene located at Xp22.12, which encodes Ribosomal S6 Kinase 2 (RSK2). Here we analyzed RPS6KA3 in three unrelated CLS patients including one from the historical Coffin-Lowry syndrome family and found two novel mutations. To date, over 140 mutations in RPS6KA3 have been reported. However, the etiology of the very first familial case, which was described in 1971 by Lowry with detailed phenotype and coined the term CLS, has remained unknown. More than 40 years after the report, we succeeded in identifying deposited fibroblast cells from one patient of this historic family and found a novel heterozygous 216 bp in-frame deletion, encompassing exons 15 and 16 of RPS6KA3. Drop episodes in CLS patients were reported to be associated with truncating mutations deleting the C-terminal kinase domain (KD), and only one missense mutation and one single basepair duplication involving the C-terminal KD of RSK2 in the patients with drop episode have been reported thus far. Here we report the first in-frame deletion in C-terminal KD of RPS6KA3 in a CLS patient with drop episodes.

A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies

“…The digital findings and the micropenis are yet to be ascribed to specific gene(s) at 11p11.2 region. Interestingly, tapering fingers is a phenotypic feature also observed in Coffin–Lowry syndrome [Nishimoto et al, ], which shares overlapping phenotypes of developmental delay and craniofacial anomalies with PSS. Micropenis has been observed in several other male patients with 11p11.2 microdeletions [Wakui et al, ].…”

“…Blood samples obtained from patient DGDP262 and his mother were used to create lymphoblastoid cell lines as reported [Nishimoto et al, ].…”

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

“…When CHEK2 mutation occurs, the coding kinase is inactivated and the damaged DNA cannot repair, following which abnormal DNA replicates uncontrollably, leading to the cancer (18,19). As primary forms of mutations in the malignant tumor, missense mutations and truncated mutants lead to a significant decrease or even the complete loss of CHEK2 kinase activity (20,21). For CHEK2, the four gene mutation sites, 1100delc, IVS2G>A, del5395 and 1157T, have been identified (22).…”

Identification of the miRNA-target gene regulatory network in intracranial aneurysm based on microarray expression data

“…Moreover, RPS6KA3 has been suggested to be associated with Coffin-Lowry syndrome, which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities (38). Molecular evidence from previous studies has revealed that RPS6KA3 may regulate neurotransmitter release by activating phospholipase D production of lipids required for exocytosis and that RPS6KA3 may also function as a proto-oncogene in multiple types of cancer targeted by corresponding miRNA (39,40).…”