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].