<unk>  describes a group of<unk> s caused by different mutations in<unk>  related genes. Severe deficiency of pulmonary<unk>  due to disturbed<unk>  of any of these proteins can lead to some form of interstitial lung disease in newborns and adults. These conditions share similar pathophysiology and overlapping phenotypes because<unk>  gene products interactively communicate and control one another. Thus,<unk>  of a<unk>  protein, or relating protein, generates deficiencies of others. SFTPB mutations Most disease-causing mutations in SFTPB result in a complete lack of mature SP-B protein . Lung disease is inherited in an autosomal recessive manner, requiring mutations in both alleles.<unk>  produced by infants with SP-B deficiency is abnormal in composition and does not function normally in lowering surface tension. More than 40 different mutations along the length of SFTPB gene have been accounted for in<unk> . SFTPB mutations are inherited in autosomal recessive fashion, loss-of-function mutation on both alleles are required for full expression of disease. About 2/3 or 60%-70% of those accounted disease-causing alleles come from a frameshift mutation, called 121ins2, on exon 4 of SFTPB gene, which also accounts for ~65% of US cases. The rest of the mutated alleles come from nonsense, missense, splice-site mutations, and other possible insertion and deletion mutations throughout the entire gene. These mutations cause total absence or loss-of-function of SP-B and lead to imbalance in<unk>  homeostasis. Since SP-B has a major role in<unk>  biogenesis and spreading of<unk>  and lipid layer, any disruption to existence of SP-B results in ineffective respiration and lethal pulmonary conditions at birth. Pathology manifestation in full-term infant resembles characteristics of newborn with Respiratory Distress Syndrome. Imaging of epithelial type II cells with SP-B deficiency shows immature lamellar bodies without tightly packed membranes, but rather with loose and unorganized membranes. The ratio of phospholipid-protein also decreases with abnormal phospholipids. In addition,<unk>  collected from SP-B deficiency epithelial type II cells is not as effective in lowering surface tension and creating film as normal<unk> . Immunohistochemical features of SP-B deficiency show decreased levels of proSP-B and SP-B proteins, along with increased presence of immuno protein SP-A and partially processed intermediate peptides of proSP-C. Appearance of partially processed proSP-C shows significance of mature SP-B in biogenesis and processing of SP-C. Absences of both proSP-B and SP-B proteins are observed in frameshift and nonsense mutations of SFTPB, while low level of proSP-B is detected in missense, in-frame deletionof insertion mutations. However, these mutations prevent proSP-B from fully mature into SP-B, resulting in deficiency of SP-B and<unk> . SFTPC mutations Familial cases of SP-C<unk>  are inherited in an autosomal dominant pattern, although the onset and severity of lung disease are highly variable, even within the same family. More than 40 distinct mutation variations in SFTPC gene have also been described in patients. Wild-type SP-C proteins are embedded inside the phospholipid bilayer of epithelial type II cell and function to generate and maintain monolayer of<unk>  on alveolar surface. Individuals with mutated SFTPC genes tend to manifest lung diseases in late childhood or adulthood. Mutated alleles are inherited in autosomal dominant fashion, although de novo mutations can also cause sporadic emergence of diseases. The age of onset and severity vary significantly among patients with SFTPC mutations, some only manifest symptoms in fifth or sixth decade. Most of these mutations are missense, but there have been recordings of frameshift, splice-site mutations, together with small insertions or deletions along the carboxyl terminal of SFTPC. Mutations in SFTPC gene are thought to prevent proSP-C peptides from being fully processed into mature SP-C proteins. ProSP-C proteins tend to self-accumulate along the secretory pathway, due to high hydrophobic nature, and may activate cellular destruction response. SFTPC mutations cause proSP-C proteins to aggregate and misfold during secretory process. These folded proteins trigger unfolded protein response (UPR) and cellular apoptosis to get rid of clusters of mutated peptides. Patients with SP-C<unk>  show lack of mature SP-C in epithelial type II cells and up-regulation of UPR. SFTPC mutation with highest occurrence frequency is substitution of threonine for isoleucine in codon 73, termed I73T, found in more than 25% of patients with SP-C related disorders. Staining of proSP-C shows diffuse staining strictly in cytoplasm and accumulation of immunoreactive substances surrounding the nucleus. Evaluation of diseases related to SFTPC mutations show association with chronic parenchymal lung disease. ABCA3 mutations Mutations in ABCA3 appear to be the most common cause of genetic<unk><unk>  in humans. The mutations result in a loss of or reduced function of the ABCA3 protein, and are inherited in an autosomal recessive manner . There are more than 150 different mutations throughout ABCA3 gene with various allelic heterogeneity, making it the biggest class of genetic cause of<unk><unk> . Like SP-B deficiency, ABCA3 mutations are inherited in autosomal recessive trait. Mutations of ABCA3 consist of missense, nonsense, frameshift, splice-cite, insertion or deletion. These mutations are classified into two types of ABCA3 mutations, those that preclude normal trafficking of ABCA3 from ER to lamellar membrane, and those that affect ATP-binding ability of ABCA3 needed for phospholipid transportation. Due to its roles in lamellar body biogenesis and maturation of<unk>  proteins, epithelial type II cells with altered ABCA3 exhibit premature lamellar bodies and damaged maturation of SP-B/SP-C.<unk>  samples from patients with ABCA3 deficiency do not lower surface tension as effectively. Affected surface tension ability results from incomplete formation of lamellar bodies, due to lack of lipid influx by ABCA3. Immunostaining of SP-B in ABCA3 patients show decreased level of mature SP-B and impaired process of proSP-B to SP-B, thus, confirming why ABCA3<unk>  leads to severe<unk> .
Surfactant metabolism dysfunction
Congenital pulmonary airway malformation
Hypoplastic right heart syndrome
Humoral immune deficiency
Vocal cord dysfunction
Anomalous pulmonary venous connection
Hypoplastic left heart syndrome
Upper airway resistance syndrome