Ehlers-Danlos syndrome kyphoscoliotic type 2 caused by mutations in the FKBP14 gene: an analysis of five cases

Abstract

Background. This study deals with a rare (orphan) monogenic connective tissue disorder - Ehlers-Danlos syndrome kyphoscoliotic type 2 (EDSKS2). Kyphoscoliotic type 2 Ehlers-Danlos syndrome is an autosomal recessive disorder caused by mutations in the FKBP14 gene (7p14.3), which encodes the FKBP22 protein. According to the 2017 classification, this type is in group seven - collagen spatial structure and cross-linking defects. We present results of clinical examination and molecular genetic analysis for five patients with age varying from two to fifteen years. Methods. Five patients were examined using clinical and laboratory methods. DNA samples used for the analysis were extracted from whole blood samples using a Wizard® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol. Results. The major clinical findings were kyphoscoliosis, early motor development delay, muscular weakness, hypotonia and hearing loss. Molecular genetic analysis detected a homozygous c.362dupC duplication in exon 3 of the FKBP14 gene in all five patients. This mutation is common in various countries. Differential diagnostics were carried out to exclude other Ehlers-Danlos syndrome types and myopathies. Conclusions. Literature analysis and examination of five EDSKS2 patients demonstrated the involvement of major organs and systems, such as joints, spine, muscles, cardiovascular system, respiratory system, hearing, and vision, into the pathological process. Kidney mobility increases and nephroptosis seems to be secondary caused by muscular weakness. During molecular genetic analysis, to verify EDSKS2 it is recommended to initially search for the c.362dupC duplication, which appears to be common in European countries, including Russia.

Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : Further insights into the phenotypic spectrum and pathogenic mechanisms

“…This study reports the clinical and molecular characteristics of three nonrelated individuals with kEDS-FKBP14 and brings the total number of reported individuals to 40 individuals from 36 families (Alazami et al, 2016;Aldeeri et al, 2014;Bursztejn et al, 2017;Castori et al, 2018;Conversano et al, 2020;Dordoni et al, 2016;Giunta et al, 2018;Murray et al, 2014;Ruiz-Botero et al, 2019;Sainio et al, 2022;Semyachkina et al, 2021). Mild to moderate learning problems and/or speech problems have been reported in 22.5% (n = 9) and notably, 77.8% of these individuals (n = 7, not reported in 1 and absent in 1) also had hearing impairment which could negatively influence language development.…”

“…This study reports the clinical and molecular characteristics of three nonrelated individuals with kEDS‐ FKBP14 and brings the total number of reported individuals to 40 individuals from 36 families (Alazami et al, 2016; Aldeeri et al, 2014; Bursztejn et al, 2017; Castori et al, 2018; Conversano et al, 2020; Dordoni et al, 2016; Giunta et al, 2018; Murray et al, 2014; Ruiz‐Botero et al, 2019; Sainio et al, 2022; Semyachkina et al, 2021). The clinical manifestations of the individuals in this study and a detailed literature overview of the reported phenotypes are summarized in Table 1.…”

“…In 2012, Baumann et al (2012) first reported six individuals with a phenotype very similar to kEDS-PLOD1 (but with normal LP/HP ratios) in whom biallelic pathogenic variants in FKBP14, encoding the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22kDa (FKBP22), were identified. Since then, 37 individuals from 33 families with kEDS-FKBP14 (MIM# 614557) have been reported in literature (Alazami et al, 2016;Aldeeri et al, 2014;Bursztejn et al, 2017;Castori et al, 2018;Conversano et al, 2020;Dordoni et al, 2016;Giunta et al, 2018;Murray et al, 2014;Ruiz-Botero et al, 2019;Sainio et al, 2022;Semyachkina et al, 2021).…”

Prognostic Value of Association of Copy Number Alterations and Cell-Surface Expression Markers in Newly Diagnosed Multiple Myeloma Patients

“…gDNA was extracted with the Wizard ® Genomic DNA Purification Kit (Promega Corp., Madison, WI, USA) according to the manufacturer’s instructions [ 76 , 77 ]. The quality and quantity of isolated gDNA was assessed using NanoDrop 2000 (Thermo Fisher Scientific, Waltham, MA,, USA).…”

Local Net Charge State of Collagen Triple Helix Is a Determinant of FKBP22 Binding to Collagen III

“…Moreover, mutations in members of this molecular ensemble can also cause collagen-related connective tissue disorders, which have already been shown to be a cause of OI, establishing the paradigm of a genetic pathway extending from inside the cell to the extracellular matrix [14][15][16][17][18][19]. Similarly, in EDS, mutations in the FKBP14 gene encoding FKBP22 (FK506 Binding Protein 22 kDa) result in kyphoscoliotic EDS [20][21][22][23][24][25]. FKBP22 acts as a molecular chaperone for type III collagen and catalyzes collagen folding through prolyl isomerase activity in the ER [26,27].…”