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.