Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

BACKGROUND: Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant. METHODS: Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis. RESULTS: On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans. CONCLUSIONS: This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.

A schizophrenia associated CMYA5 allele displays differential binding with desmin.

CMYA5 is a candidate gene for schizophrenia because of the genetic association of variant rs10043986 (C > T) to this severe mental disorder. Studies of CMYA5 and its gene product, myospryn, in the brain and neuronal cells have not been previously reported. The SNP rs10043986 changes the 4,063rd amino acid from Pro to Leu, which is likely to alter protein function. To understand its potential role in the brain, we examined the neuronal expression of myospryn and its binding partner, desmin, an intermediate filament (IF) protein, and investigated how the two alleles of myospryn affect its binding to desmin. Myospryn and desmin are shown to be expressed in the brain and myospryn is shown to localize to the cytoplasm and nucleus of myoblast, neuroblastoma, and glioblastoma cell lines. Peripherin and vimentin, known brain IF proteins, have high protein similarity to desmin but were found not to interact with myospryn using yeast two-hybrid (Y2H). Using a quantitative Y2H assay and surface plasmon resonance, the T allele (Leu) of rs10043986 was found to have stronger binding to desmin than the C allele (Pro). Based on findings described in this report, we hypothesize that the interaction between myospryn to IF provides structural support and efficient rearrangement of the cytoskeleton network during early neuritogenesis.