Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) 2B and mild DA in two Chinese families

Abstract

BackgroundDistal arthrogryposis (DA) is a group of clinically and genetically heterogeneous disorders that involve multiple congenital limb contractures and comprise at least 10 clinical subtypes. Here, we describe our findings in two Chinese families: Family 1 with DA2B (MIM 601680) and Family 2 with mild DA.MethodsTo map the disease locus, two-point linkage analysis was performed with microsatellite markers closed to TPM2, TNNI2/TNNT3 and TNNC2. In Family 1, a positive LOD (logarithm of odds) score was only obtained at the microsatellite marker close to TPM2 and mutation screening was performed using direct sequencing of TPM2 in the proband. In Family 2, for the LOD score that did not favor linkage to any markers, whole-exome sequencing (WES) was performed on the proband. PCR–restriction fragment length polymorphism (RFLP) and bioinformatics analysis were then applied to identify the pathogenic mutations in two families. In order to correlate genotype with phenotype in DA, retrospective analyses of phenotypic features according to the TPM2 and PIEZO2 mutation spectrums were carried out.ResultsA heterozygous missense mutation c.308A > G (p.Q103R) in TPM2 in Family 1, and a novel variation c.8153G > A (p.R2718Q) in PIEZO2 in Family 2 were identified. Each of the two novel variants was co-segregated with the DA manifestations in the corresponding family. Bioinformatics analysis from several tools supported the pathogenicity of the mutations. Furthermore, our study suggests that there is no relation between the types or locations of TPM2 mutations and the clinical characteristics, and that different inheritance modes and mutation types concerning PIEZO2 cause distinct clinical manifestations.ConclusionsWe report two novel mutations within TPM2 and PIEZO2 responsible for DA2B and mild DA in two Chinese families, respectively. Our study expands the spectrum of causal mutations in the TPM2 and PIEZO2 genes.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0692-8) contains supplementary material, which is available to authorized users.

Caenorhabditis elegans PIEZO channel coordinates multiple reproductive tissues to govern ovulation

“…Individuals diagnosed with Dehydrated Hereditary Stomatocytosis (DHSt) were found to have a missense mutation in a conserved arginine residue (R2488Q) of PIEZO1. The orthologous residue (R2718L/P) was also mutated in PIEZO2 in individuals with Distal Arthrogryposis type 5 (DA5) ( Andolfo et al, 2013 ; Coste et al, 2013 ; Li et al, 2018 ; McMillin et al, 2014 ).…”

“…Previous studies have shown that these arginine changes are functioning as gain-of-function mutations in their respective PIEZO protein ( Albuisson et al, 2013 ; Coste et al, 2013 ; Li et al, 2018 ; McMillin et al, 2014 ). Sequence alignment indicated that R2405 in C. elegans PEZO-1 is the arginine residue homologous to both R2488 in human PEIZO1 and R2718 in human PIEZO2 ( Figure 9A ).…”

“…PIEZO2 primarily functions as a key mechanotransducer for light touch, proprioception and breathing ( Nonomura et al, 2017 ; Woo et al, 2015 ; Woo et al, 2014 ). Mutations in both human PIEZO1 and human PIEZO2 have been identified among patients suffering from channelopathy diseases, such as dehydrated hereditary stomatocytosis (DHSt), generalized lymphatic dysplasia (GLD), and distal arthrogryposis type 5 (DA5), in which osmoregulation is disturbed ( Albuisson et al, 2013 ; Andolfo et al, 2013 ; Bae et al, 2013 ; Coste et al, 2013 ; Li et al, 2018 ; Lukacs et al, 2015 ; McMillin et al, 2014 ; Zarychanski et al, 2012 ). Loss-of-function mutations in the PIEZO1 gene cause autosomal recessive congenital lymphatic dysplasia, whereas gain-of-function mutations lead to autosomal dominant stomatocytosis ( Alper, 2017 ).…”

Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene

“…Intellectual disability is a typical symptom of Marden-Walker syndrome caused by PIEZO2 gain-of-function variants (McMillin et al, 2014 ). This syndrome typically involves congenital contractures of hands and feet, or cleft palate, ophthalmoplegia, ptosis, and cerebellar malformations (Li et al, 2018 ). We could not exclude the partial clinical overlap with this syndrome.…”

Anin vivoapproach to characterize novel variants associated with musculoskeletal disorders

“…TPM2 variants are causative of DA type 1 (DA1) (Sung et al, 2003), which is characterized by contractures of the hands and feet including permanently bent fingers (camptodactyly) and clubfoot (talipes equinovarus) (Bamshad et al, 2009). TPM2 variants are also associated with DA type 2B (DA2B) (Li et al, 2018;Tajsharghi et al, 2007a), which is characterized by facial abnormalities in addition to contractures of the extremities (Bamshad et al, 2009). DA patients often show hypotonia (Marttila et al, 2014;Mroczek et al, 2017), arguing skeletal muscle dysfunction contributes to the overall disease mechanism.…”