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Eur J Hum Genet. 2019 Jul 5. doi: 10.1038/s41431-019-0464-8. [Epub ahead of print]

Expansion of B4GALT7 linkeropathy phenotype to include perinatal lethal skeletal dysplasia.

Author information

1
Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, 43205, USA. theresa.mihalicmosher@nationwidechildrens.org.
2
Department of Pediatrics, The Ohio State University, Columbus, OH, 43205, USA. theresa.mihalicmosher@nationwidechildrens.org.
3
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 43205, USA. theresa.mihalicmosher@nationwidechildrens.org.
4
Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA.
5
Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, 43205, USA.
6
Department of Pediatrics, The Ohio State University, Columbus, OH, 43205, USA.
7
Maternal-Fetal Medicine, Miami Valley Hospital, Dayton, OH, 45409, USA.
8
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
9
Center for Cardiovascular Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA.

Abstract

Proteoglycans have a core polypeptide connected to glycosaminoglycans (GAGs) via a common tetrasaccharide linker region. Defects in enzymes that synthesize the linker result in a group of autosomal recessive conditions called "linkeropathies". Disease manifests with skeletal and connective tissue features, including short stature, hyperextensible skin, and joint hypermobility. We report a family with three affected pregnancies showing short limbs, cystic hygroma, and perinatal death. Two spontaneously aborted; one survived 1 day after term delivery, and had short limbs, bell-shaped thorax, 11 ribs, absent thumbs, and cleft palate. Exome sequencing of the proband and one affected fetus identified compound heterozygous missense variants, NM_007255.3: c.808C>T (p.(Arg270Cys)) and NM_007255.3: c.398A>G (p.(Gln133Arg)), in B4GALT7, a gene required for GAG linker biosynthesis. Homozygosity for p.(Arg270Cys), associated with partial loss of B4GALT7 function, causes Larsen of Reunion Island syndrome (LRS), however no previous studies have linked p.(Gln133Arg) to disease. The p.(Gln133Arg) and p.(Arg270Cys) variants were transfected into CHO pgsB-618 cells. High protein expression of p.(Gln133Arg) was found, with mislocalization, compared to p.(Arg270Cys) that had a normal Golgi-like pattern. The p.(Gln133Arg) had almost no enzyme activity and little production of heparan sulfate GAGs, while p.(Arg270Cys) only had 17% of wild-type activity. These findings expand the phenotype of B4GALT7-related linkeropathies to include lethal skeletal dysplasia due to more severe loss of function.

PMID:
31278392
DOI:
10.1038/s41431-019-0464-8

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