NovelFOXF1Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Hereditary interstitial lung diseases manifesting in early childhood in Japan

“…Approximately 80% of ACD/MPV cases have anomalies of other organs, particularly of the cardiovascular, gastrointestinal, and genitourinary systems (35). The previous study (19) substantiates the suggestion that mutations in FOXF1 lead to manifestation of ACD/MPV and that this transcription factor is involved in development of the pulmonary, cardiovascular, gastrointestinal, and genitourinary systems. Although rare, late presentation has been reported (36,37) with affected patients typically developing lung dysfunction and pulmonary hypertension a few hours after birth.…”

“…Among the 12 genetic variations detected in the eight cases (cases 1-8 in Table 3), two in cases 1 and 6 were reported previously (18,19). To our knowledge, 10 other mutations in six cases (cases 2-5, 7, and 8) have not been reported to date, i.e., four SFTPC mutations of heterozygous p.Gln145fs, heterozygous p.Lys63Glu, p.Ser72Asn, and p.Gly100Ala, and six ABCA3 mutations of p.Arg1583Trp, p.Val1495CysfsX21, p.Pro73Leu, p.Gly1205Arg, p.Thr761Met, and p.Ala1362Val.…”

“…There were two patients with ACD/MPV in this study, and one of them had a FOXF1 mutation (heterozygous p.Leu300ArgfsX79) which is listed in a recent report (19). Approximately 80% of ACD/MPV cases have anomalies of other organs, particularly of the cardiovascular, gastrointestinal, and genitourinary systems (35).…”

A Novel Mutation in FOXF1 Gene Associated with a Delayed Presentation of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

“…Therefore, Arginine 86 FOXF1 mutations may have a predictive value for delayed presentation of ACD/MPV. Although overall significance of FOXF1 mutations for cellular functions of FOXF1 protein and pulmonary vascular development remains unclear, our report together with previous data suggest a critical importance of Arginine 86 for pathogenesis of ACD/MPV [3].…”

“…The c.257G > C; p.R86P FOXF1 mutation resulted in a single aminoacid substitution of evolutionary conserved Arginine 86 to Proline (Figure 3(a)). Arginine 86 is located in FOXF1 DNA-binding domain (Figure 3(b)), which is frequently mutated in ACD/MPV patients [3]. This mutation was not detected in patient's parents, suggesting of a de novo variant.…”