A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature..

INTRODUCTION: Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption.

CASE: A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function.

CONCLUSION: This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.

Medienart:	E-Artikel

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	Zur Gesamtaufnahme - volume:112
Enthalten in:	Calcified tissue international - 112(2023), 4 vom: 28. Apr., Seite 518-523

Sprache:	Englisch

Beteiligte Personen:	Ryabets-Lienhard, Anna [VerfasserIn] Panjawatanan, Panadeekarn [VerfasserIn] Vogt, Kyle [VerfasserIn] Ji, Jianling [VerfasserIn] Georgia, Senta [VerfasserIn] Pitukcheewanont, Pisit [VerfasserIn]

Links:	Volltext

Themen:	Case Reports Cell Cycle Proteins Child EC 3.6.5.1 FAM111B gene FAM111B protein, human FAM111B protein modeling GNAS gene GTP-Binding Protein alpha Subunits, Gs Journal Article Male POIKTMP Primary heterotopic ossification Progressive osseous heteroplasia

Anmerkungen:	Date Completed 21.03.2023 Date Revised 27.03.2023 published: Print-Electronic Citation Status MEDLINE

doi:	10.1007/s00223-022-01053-0

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	NLM350867925