Mutations and altered expression ofSERPINF1in patients with familial otosclerosis

Abstract

Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, little progress has been made in identifying disease-causing genes. Here, we used whole-exome sequencing in four families exhibiting dominantly inherited otosclerosis to identify 23 candidate variants (reduced to 9 after segregation analysis) for further investigation in a secondary cohort of 84 familial cases. Multiple mutations were found in the SERPINF1 (Serpin Peptidase Inhibitor, Clade F) gene which encodes PEDF (pigment epithelium-derived factor), a potent inhibitor of angiogenesis and known regulator of bone density. Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function. The other three variants are all located in the 5′-untranslated region (UTR) of an alternative spliced transcript SERPINF1-012. RNA-seq analysis demonstrated that this is the major SERPINF1 transcript in human stapes bone. Analysis of stapes from two patients with the 5′-UTR mutations showed that they had reduced expression of SERPINF1-012. All three 5′-UTR mutations are predicted to occur within transcription factor binding sites and reporter gene assays confirmed that they affect gene expression levels. Furthermore, RT-qPCR analysis of stapes bone cDNA showed that SERPINF1-012 expression is reduced in otosclerosis patients with and without SERPINF1 mutations, suggesting that it may be a common pathogenic pathway in the disease.

Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families

“…Missense variants in SERPINF1 were found to underlie otosclerosis in three families (Ziff et al. ), but our patient aged 7 years had no hearing impairment.…”

Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population

“…This is likely to be due to the reduced power of linkage studies in the presence of incomplete penetrance. A more recent study using a whole exome sequencing approach identified multiple individuals with rare mutations in SERPINF1 in a cohort of familial patients (Ziff et al 2016 ). Functional studies suggest these mutations affect expression of an alternatively spliced transcript which is normally highly expressed in stapes bone.…”

Identification of four hub genes as promising biomarkers to evaluate the prognosis of ovarian cancer in silico

“…Moreover, researchers investigated patients with retinoblastoma and found that pathological cells in their body rely on SERPINF1, with its contribution to neuron differentiation. Mutations of this gene are also detected in osteogenesis imperfecta, type VI [39,40]. Individuals suffering from type II diabetes have increasing circulating level of PEDF, confirmed a strong association with this gene at genome-wide significance [41,42].…”