Pathophysiology of inherited protein surfactant deficiency
Surfactant protein deficiency syndrome (SPDS) is a group of diseases caused by genetic mutations ofSFTPB, SPTPC, ABCA3 and TTF1 genes. Surfactant protein deficiencies are rare; the frequency of SFTPB deficiency was first described in 1993, as 1 in 1,000,000, while the frequency of SFTPC, ABCA3 andTTF1 deficiencies remain unknown[34].
The SFTPB gene is located on chromosome 2 with over 30 known pathogenic mutations that occurs as nonsense, missense, frameshift and splice site mutations causing autosomal recessive inherited SP-B deficiency[35]. This leads to abnormal surfactant composition and impaired function that results in increased alveolar surface tension. Infants with SP-B deficiency also lack mature SP-C due to incomplete and aberrant formation of pro SP-C protein[36] that further reduces the effectiveness of their surfactant[37]. The most common mutation associated with SP-B deficiency is the c.397delCinsGAA (previously known as 121ins2) mutation which occurs in 70% of patients with surfactant protein B deficiency -primarily in infants of northern European descend[38, 39]. This mutation occurs as a GAA substitution for C at the genomic position g.1549 in codon 121 which then results in an unstable transcript and an absence on pro SP-B protein[40].
The SFTPC gene is located on chromosome 8 with over 50 dominant mutations that may arise de novo in 55% of cases or have variable penetration[41]. These mutations can occur as missense, frameshift, insertion, deletion, and splice site mutations with the most common mutation p.Ile73Thr (or c.218 T>C), occurring in 25% of patients with SP-C mutations[42]. The SFTPC gene mutations can be divided into 3 groups: 1) Mutations in theBRICHOS domain which has been implicated with various other illnesses such as dementia, malignancies and SP-C deficiency[43]. These type of mutations (examples include SP-CL188Qand SP-CΔexon4 ) [42, 44]causes misfolding of SP-C pro-proteins and formation of cytosolic aggregates which then leads to endoplasmic reticulum stress, cell death, apoptosis and lung injury. 2) non- BRICHOS mutations (example include SP-CI73T ) that allows trafficking to the endosomal system without misfolded protein aggregation or endoplasmic reticulum stress but causes the formation of large autophagic vacuoles and the accumulation of defective mitochondria[45]. 3) N- terminal mutation that causes unfolding of SP-C and retention of amyloid fibrils on the endoplasmic reticulum[46-48]. .
The ABCA3 gene is located on chromosome 16. ABCA3 deficiency is inherited in an autosomal recessive fashion with over 150 mutations identified. The most common mutation, p.Glu292Val (or p.E292V, c.875 A>T) accounts for under 10% of patients[49]. The frequency of ABCA3 deficiency has been estimated in individuals from European descent to be 1 in 3100 and 1 in 18000 in individuals from African descent[50]. Mutations of the ABCA3 gene can lead to production of abnormal lamellar bodies and to abnormal SP-B and SP-C proteins, although the exact reason for the effect on SP-B and SP-C remains unclear[50]. Kröner et al reviewed 40 patients with two disease causing ABCA3 mutations and identified 2 major phenotypes namely those that died within the first 6 months or those that survive longer [51]. Patients with frameshift or nonsense ABCA3 mutations resulting in null/null genotypes are more likely to have a neonatal presentation and poor prognosis, while the presentation and prognosis is less predictable for other types of mutations resulting in null/other or other/other [52].
Mutations of the NKX2.1 gene causing inactivation of at least 1 allele results in reduced DNA binding and transcription which leads to reduced TTF1 and reduced production of SP-B, SP-C and ABCA3. These autosomal dominant mutations usually occur de novo and sporadically and may result in low alveolar count and may adversely affect airway development[53]. TTF-1 is also expressed in the thyroid and forebrain and plays a role in cellular function and thus mutations of NKX2.1 may result in a multisystemic presentation[54].