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A novel FLNA variant in a fetus with skeletal dysplasia.

ABSTRACT: Otopalatodigital spectrum disorder (OPDSD) is characterized by variable phenotypes, including skeletal dysplasia, and is caused by pathogenic variants in filamin A-encoding FLNA. FLNA variants associated with lethal OPDSD primarily alter the CH2 subdomain of the ABD of FLNA. Herein, we report a novel FLNA mutation in a fetus with severe skeletal dysplasia in a pregnant multigravida female with a history of repeated miscarriages and terminations.

SUBMITTER: Oshina K

PROVIDER: S-EPMC9744731 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A novel FLNA variant in a fetus with skeletal dysplasia.

Oshina Kyoko K Kamei Yoshimasa Y Hori Asuka A Hasegawa Fuyuki F Taniguchi Kosuke K Migita Ohsuke O Itakura Atsuo A Hata Kenichiro K

Human genome variation 20221213 1

Otopalatodigital spectrum disorder (OPDSD) is characterized by variable phenotypes, including skeletal dysplasia, and is caused by pathogenic variants in filamin A-encoding FLNA. FLNA variants associated with lethal OPDSD primarily alter the CH2 subdomain of the ABD of FLNA. Herein, we report a novel FLNA mutation in a fetus with severe skeletal dysplasia in a pregnant multigravida female with a history of repeated miscarriages and terminations. ...[more]

PMID: 36509760

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Project description:BackgroundLimb bones develop and grow by endochondral ossification, which is regulated by specific cell and molecular pathways. Changes in one or more of these pathways can have severe effects on normal skeletal development, leading to skeletal dysplasias. Many skeletal dysplasias are known to result from mis-expression of major genes involved in skeletal development, but the etiology of many skeletal dysplasias remains unknown. We investigated the morphology and development of a mouse line with an uncharacterized mutation exhibiting a skeletal dysplasia-like phenotype (Nabo).MethodsWe used µCT scanning and histology to comprehensively characterize the phenotype and its development, and to determine the developmental stage when this phenotype first appears.ResultsNabo mice have shorter limb elements compared to wildtype mice, while clavicles and dermal bones of the skull are not affected. Nabo embryos at embryonic stage E14 show shorter limb cartilage condensations. The tibial growth plate in Nabo mice is wider than in wildtype, particularly in the proliferative zone, however proliferative chondrocytes show less activity than wildtype mice. Cell proliferation assays and immunohistochemistry against the chondrogenic marker Sox9 suggest relatively lower, spatially-restricted, chondrocyte proliferation activity in Nabo. Bone volume and trabecular thickness in Nabo tibiae are also decreased compared to wildtype.DiscussionOur data suggest that the Nabo mutation affects endochondral ossification only, with the strongest effects manifesting in more proximal limb structures. The phenotype appears before embryonic stage E14, suggesting that outgrowth and patterning processes may be affected. Nabo mice present a combination of skeletal dysplasia-like characteristics not present in any known skeletal dysplasia. Further genomic and molecular analysis will help to identify the genetic basis and precise developmental pathways involved in this unique skeletal dysplasia.

Dataset Information

A novel FLNA variant in a fetus with skeletal dysplasia.

Publications

A novel FLNA variant in a fetus with skeletal dysplasia.

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