Abstract:Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low‐density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal‐recessive OI XX in homozygous children. In the present study, whole‐exome sequencing … Show more
“…The range of the clinical presentations in individuals with biallelic pathogenic variants in MESD is striking, as it extends from a very severe peri- or prenatal lethal phenotype to one that fits into the more affected end of the original OI type IV range of Sillence (Moosa et al., 14 Stürznickel et al., 15 and this report). From these reports it is clear that heterozygosity, even for a likely null allele, is tolerated without clinical effect.…”
Section: Main Textmentioning
confidence: 62%
“… Figure 2 Structure of the MESD gene and MESD protein, pedigrees of the described families, and representation of the mutant allele sequences (A) The MESD gene consists of 3 exons (4,200 bp) and comprises 14.07 kb on chromosome 15. The cumulative frequency of the six known pathogenic MESD alleles (both this and two previous studies 14 , 15 ) are denoted with colored lollipop graphs. The pathogenic alleles included in this report are highlighted in orange, red, and blue, respectively.…”
Section: Main Textmentioning
confidence: 98%
“…Bone mineral density distribution measured by quantitative backscattered electron imaging indicated impaired and more heterogeneous matrix mineralization in the described MESD fetuses than in controls. 15 OI that results from pathogenic variants in MESD has been designated as OI type XX (MIM: 618644 ) in OMIM. Here, we present four new MESD individuals and used fibroblast studies to get additional insight into the pathogenic pathways of the MESD -related OI subtype.…”
Summary
The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (
COL1A1
or
COL1A2
). To date, two reports have linked Mesoderm Development LRP Chaperone (
MESD
) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in
MESD
were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in
MESD
were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in
MESD
: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)—which are associated with a severe form of OI—and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of
MESD
-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.
“…The range of the clinical presentations in individuals with biallelic pathogenic variants in MESD is striking, as it extends from a very severe peri- or prenatal lethal phenotype to one that fits into the more affected end of the original OI type IV range of Sillence (Moosa et al., 14 Stürznickel et al., 15 and this report). From these reports it is clear that heterozygosity, even for a likely null allele, is tolerated without clinical effect.…”
Section: Main Textmentioning
confidence: 62%
“… Figure 2 Structure of the MESD gene and MESD protein, pedigrees of the described families, and representation of the mutant allele sequences (A) The MESD gene consists of 3 exons (4,200 bp) and comprises 14.07 kb on chromosome 15. The cumulative frequency of the six known pathogenic MESD alleles (both this and two previous studies 14 , 15 ) are denoted with colored lollipop graphs. The pathogenic alleles included in this report are highlighted in orange, red, and blue, respectively.…”
Section: Main Textmentioning
confidence: 98%
“…Bone mineral density distribution measured by quantitative backscattered electron imaging indicated impaired and more heterogeneous matrix mineralization in the described MESD fetuses than in controls. 15 OI that results from pathogenic variants in MESD has been designated as OI type XX (MIM: 618644 ) in OMIM. Here, we present four new MESD individuals and used fibroblast studies to get additional insight into the pathogenic pathways of the MESD -related OI subtype.…”
Summary
The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (
COL1A1
or
COL1A2
). To date, two reports have linked Mesoderm Development LRP Chaperone (
MESD
) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in
MESD
were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in
MESD
were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in
MESD
: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)—which are associated with a severe form of OI—and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of
MESD
-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.
“…By 2019, 20 types of OI had been recognized worldwide, and 18 causative genes had been discovered ( Etich et al, 2020 ). In the past year, studies have successively reported three new causative genes for OI ( MESD , KDELR2 , and CCDC134 ) ( Dubail et al, 2020 ; van Dijk et al, 2020 ; Stürznickel and Jähn-Rickert, 2021 ), which were not included in the panel. Future studies may identify even more causative genes for OI.…”
Genetic skeletal dysplasias (GSDs) are a type of disease with complex phenotype and high heterogeneity, characterized by cartilage and bone growth abnormalities. The variable phenotypes of GSD make clinical diagnosis difficult. To explore the clinical utility of targeted exome sequencing (TES) in the diagnosis of GSD, 223 probands with suspected GSD were enrolled for TES with a panel of 322 known disease-causing genes. After bioinformatics analysis, all candidate variants were prioritized by pathogenicity. Sanger sequencing was used to verify candidate variants in the probands and parents and to trace the source of variants in family members. We identified the molecular diagnoses for 110/223 probands from 24 skeletal disorder groups and confirmed 129 pathogenic/likely pathogenic variants in 48 genes. The overall diagnostic rate was 49%. The molecular diagnostic results modified the diagnosis in 25% of the probands, among which mucopolysaccharidosis and spondylo-epi-metaphyseal dysplasias were more likely to be misdiagnosed. The clinical management of 33% of the probands also improved; 21 families received genetic counseling; 4 families accepted prenatal genetic diagnosis, 1 of which was detected to carry pathogenic variants. The results showed that TES achieved a high diagnostic rate for GSD, helping clinicians confirm patients’ molecular diagnoses, formulate treatment directions, and carry out genetic counseling. TES could be an economical diagnostic method for patients with GSD.
“…In 2021, Stürznickel et al reported perinatal lethal phenotype of OI type XX in three stillbirths from the same family. Twelve unrelated patients and six different pathogenic variants have been reported in total so far, including the four additional patients reported by Tran et al very recently (Moosa et al, 2019; Stürznickel et al, 2021; Tran et al, 2021).…”
Osteogenesis imperfecta (OI) is a heterogeneous group of disorders with bone fragility. In 2019, homozygous pathogenic variants in MESD were described for the first time in five patients with severe form of OI. To date, 12 patients have been reported. The aim of this study is to report long‐term follow‐up findings of a girl with MESD variant. She had triangular face, sparse hair, wide fontanelle, blue sclera, softening of the occipital bone, congenital torticollis, and long fingers. Wormian bones, multiple rib and long bone fractures, and platyspondyly were detected in her skeletal radiographs. During the 21‐years follow‐up, intellectual disability, oligodontia, recurrent fractures, bowing of humerus, hip and knee contractures leading to crossing of the legs, swelling of the interphalangeal joints, and kyphoscoliosis were observed. Although the bisphosphonate treatment was started at 2.5 years of age, recurrent fractures continued to occur until 13 years of age. She lost her walking ability at 4.5 years of age. The final adult height was 128 cm (−6.0 SD). Homozygous c.631_632delAA (p.Lys211Glufs*19) variant in MESD was detected at 19 years of age. In conclusion, this study provides long‐term clinical and radiological findings in a patient with a very rare type of OI.
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