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Frances V White

Publications and source records attributed to Frances V White.

13 recordsLinked to original sources
PubMed2025

Lentiviral-mediated gene complementation rescues pathogenic ABCA3 variants.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein on the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease (chILD). Supportive/compassionate care or lung transplantation are the only current definitive treatments for ABCA3 deficiency and progressive respiratory failure. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell (iPSC)-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3 KO). From this line, additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus were tested: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type ABCA3. Lentiviral-mediated ABCA3 delivery to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-κB signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene addition as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.

ABCA3 deficiency↗
PubMed2006

Surfactant composition and function in patients with ABCA3 mutations.

Mutations in the gene encoding the ATP binding cassette transporter member A3 (ABCA3) are associated with fatal surfactant deficiency. ABCA3 lines the limiting membrane of lamellar bodies within alveolar type-II cells, suggesting a role in surfactant metabolism. The objective of this study was to determine the surfactant phospholipid composition and function in patients with mutations in the ABCA3 gene. Bronchoalveolar lavage (BAL) fluid was analyzed from three groups of infants: 1) Infants with ABCA3 mutations, 2) infants with inherited surfactant protein-B deficiency (SP-B), and 3) patients without parenchymal lung disease (CON). Surfactant phospholipid profile was determined using two-dimensional thin-layer chromatography, and surface tension was measured with a pulsating bubble surfactometer. Phosphatidylcholine comprised 41 +/- 19% of the total phospholipid in the BAL fluid of the ABCA3 group compared with 78 +/- 3% and 68 +/- 18%, p = 0.008 and 0.05, of the CON and SP-B groups, respectively. Surface tension was 31.5 +/- 9.3 mN/m and was significantly greater than CON but no different from SP-B. We conclude that mutations in ABCA3 are associated with surfactant that is deficient in phosphatidylcholine and has decreased function, suggesting that ABCA3 plays an important role in pulmonary surfactant phospholipid homeostasis.

ATP-Binding Cassette Transporters↗
PubMed2006

Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation.

OBJECTIVES: Biliary atresia (BA), a congenital idiopathic obliterative cholangiopathy, rapidly leads to liver cirrhosis and liver failure if untreated. A timely Kasai portoenterostomy (KP) variably alters this natural history. We evaluated liver fibrogenesis by the intensity of alpha-smooth-muscle actin (SMA) expression, which is a marker for hepatic stellate cell activation. We hypothesized that liver fibrogenesis as determined by intensity of alpha-SMA is already progressing at the time of KP, is related to age and degree of fibrosis at KP, and predicts outcome after KP. METHODS: BA patients at KP (n = 22, age 22-84 days, median 59) had wedge liver biopsies assessed by quantitative morphometry of immunohistochemistry for alpha-SMA expression. Fibrosis was scored by blinded pathologists. Outcome, reflected by conjugated bilirubin concentration 3 months after KP (CBili3m), survival of the native liver, need for liver transplant, or death, were assessed for 2 to 10 years after KP. RESULTS: At KP, age, fibrosis score, and alpha-SMA expression were significantly correlated. Moderate-severe fibrosis and intense alpha-SMA expression was observed in 15 of 22 (68%) patients. Severe fibrosis and high alpha-SMA expression were significantly associated with CBili3m greater than 2 g/dL and unfavorable liver survival (>90% of these ultimately underwent liver transplantation or died). Conversely, those with mild fibrosis and low alpha-SMA expression had normal CBili3m and favorable liver survival. CONCLUSION: Intense liver fibrogenesis is already established in many cases of BA at the time of KP. Fibrosis scores and intensity of alpha-SMA expression may be predictors of outcome after KP and may indicate those patients who might benefit from trials of potential antifibrotic agents early in the course of BA.

Actins↗
PubMed2005

Otolaryngological manifestations of posttransplant lymphoproliferative disorder in pediatric thoracic transplant patients.

OBJECTIVE: To identify the otolaryngological manifestations of posttransplant lymphoproliferative disorder (PTLD) in pediatric heart and lung transplant recipients. METHODS: A 14-year retrospective case series review (1990-2003) of children less than 18 years of age presenting with PTLD after receiving orthotopic heart and lung transplants at St. Louis Children's hospital (St. Louis, MO, USA). RESULTS: One hundred ninety seven cardiac and 246 pulmonary transplant patients were included in this review. Thirteen heart transplant patients developed PTLD with 39% (5/13) presenting in the head and neck. Thirty-two lung transplant patients developed PTLD with 25% (8/32) presenting in the head and neck. PTLD in cardiac transplants most often presented as adenotonsillar hypertrophy or cervical lymphadenopathy. The sinonasal cavity was the most common site of head and neck PTLD in pulmonary transplants patients. CONCLUSIONS: This study suggests that head and neck involvement is more common than currently reported in the literature. As thoracic organ transplants become more frequent in children, otolaryngologists caring for this population should maintain a high index of suspicion for any suggestive findings. Evaluation must include tissue biopsy, as histopathologic examination is required for diagnosis.

Adenoids↗
PubMed2005

Desmoplastic fibroma of the mandible in an infant.

We report the CT and MR imaging findings of a case of a desmoplastic fibroma of the mandible in a 6-month-old girl who presented with a rapidly enlarging facial mass and who represents one of the youngest reported children with this rare tumor. Although imaging is non-specific and these lesions are best distinguished histologically, the desmoplastic fibroma should be considered when there is an occurrence of any bubbly or cystic expansile mandibular lesion presenting in childhood.

Diagnosis, Differential↗
PubMed2005

Ciliated hepatic foregut cyst in a young child.

Ciliated hepatic foregut cysts are a rare entity usually found in adults. We present a case of a 3-year-old boy incidentally noted to have a radiographically complex liver cyst on computed tomographic scan. Given the complex appearance, the cyst was excised. Pathology revealed a ciliated hepatic foregut cyst. This is the second child and youngest patient affected with this lesion reported in the literature. The etiology of the lesion and an argument for surgical removal in pediatric patients are presented.

Age Factors↗
PubMed2005

Sialidosis presenting as severe nonimmune fetal hydrops is associated with two novel mutations in lysosomal alpha-neuraminidase.

Sialidosis is a lysosomal storage disease characterized by accumulation of sialylated oligosaccharides in tissues, blood and urine and is caused by mutations in the gene for lysosomal alpha-neuraminidase (NEU1). There is wide variability in the age of onset and severity of symptoms in sialidosis. We report here a case of sialidosis due to novel mutations in NEU1 presenting as severe nonimmune hydrops fetalis.

Codon, Nonsense↗
PubMed2004

Viral diseases of the liver in children: diagnostic and differential diagnostic considerations.

This review summarizes the general histologic features of acute and chronic hepatitides and highlights those morphologic findings that may suggest or be diagnostic of a specific agent or etiology. The main epidemiologic, clinical, and pathologic features of the hepatotropic viruses are discussed, with an emphasis on pediatric studies and the differential diagnosis of hepatitis in childhood.

Adult↗
PubMed2004

Hepatic fibrosis and survival in biliary atresia.

In biliary atresia, progression of hepatic fibrosis before the Kasai portoenterostomy may explain why age is a major determinant of survival of the native liver. Blinded fibrosis scoring of surgical liver biopsies demonstrated that age and fibrosis correlate. Those biopsies with severe fibrosis predicted significantly worse survival.

Biliary Atresia↗
PubMed2003

Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene.

Mutations in the surfactant protein (SP)-C gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluorescence, proSP-C was aggregated within alveolar Type II cells in a compartment separate from SP-B. In airway surfactant, there was little or no mature SP-B or SP-C; SP-A content was increased. Minimum surface tension was increased (20 mN/m, normal < 5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy. This spontaneous deletion on one allele of the SP-C gene was associated with sporadic ILD and abnormalities in surfactant composition and function. We propose that a dominant negative effect on surfactant protein metabolism and function results from aggregation of misfolded proSP-C and subsequent cell injury and inflammation.

Adult↗