Understanding Idiopathic Interstitial Pneumonia: A Gene-Based Review of Stressed Lungs

Table 1

Mutated genes in IIP, expressing pulmonary cells, function, and mutational consequences.

Gene	Expressing cells in lung	Gene function	Mutated domain	Effect of mutation	Pathological process
SFTPC	AEC type II [107]	Component of surfactant fluid; Lower surface tension [107]	Linker domain associates with LB [31]	Toxic gain of function [107]	Alteration of trafficking, dysregulation of proteostasis [31]; Alteration of surfactant lipid composition [31]
			C-terminal BRICHOS domain folded in ER and GA [108]		ER stress and UPR upregulation [109–111]; Activation of immune cells [112]; Alteration of surfactant lipid composition [112]
SFTPA2	AEC type II; Clara/club cell; Submucosal gland [113–116]	Collectin (to modulate innate and adaptive immunity) [107, 117]	Carbohydrate-recognition domain [32]	Toxic gain of function [118]	Increase of ER stress [118]; UPR upregulation; [35, 119]
ABCA3	AEC type II [120]	Limiting membrane protein of lamellar body [107]	Intracellular loop, extracellular domain 2 [45, 46, 121]	Loss of function; Toxic gain of function [107]	Abnormal surfactant processing/trafficking [45, 122]; Loss of epithelial function [41]; Increase of ER stress [41, 44]
TERT	AEC type II [123]; Lung fibroblasts [124, 125]; Lung epithelial cells [126]	Enzyme in telomerase complex maintaining telomere length [127–130]	All [55, 56, 60, 131–135]	Haploinsufficiency [56, 136, 137]	Telomere shortening [55, 56, 61, 62, 124, 131, 138, 139]
TERC	AEC type II [70, 123, 140]; Lung fibroblasts [124, 125]	Template in telomerase complex [127–130]	Pseudoknot, CR4-CR5, and ScaRNA domains [55, 56, 61, 133, 139, 141, 142]	Haploinsufficiency [136, 137, 143, 144]	Telomere shortening [55, 56, 61, 124, 131, 138]
DKC1	Lung tissue [145]	Dyskerin (stabilizes template in telomerase complex) [64]	Near RNA-binding domain [64], near N-terminus [146–149]	X-linked loss of function [64]	Telomere shortening [64]; Decrease in TERC [146]
TINF2	Lung tissue [150]	Telomere maintenance by shelterin complex [151]	Exon 6 residues 269–298 [63, 152, 153]	Dominant negative [63]	Telomere shortening [63]
RTEL1	Not detectable in lungs [154, 155]	DNA helicase, telomere T-loop, and G4 unwinding [156]	Various domains, that is, helicase and harmonin [65–67, 157]	Haploinsufficiency [66]	Telomere shortening [65–67]
PARN	Lung tissue [158]	Exoribonuclease controls mRNA stability [159]	Mainly CAF1 ribonuclease domain [67]	Haploinsufficiency [67]	Telomere shortening [67]; Reduction of DKC1, TERT, TERC, and TERF1 [159]

Gene function suggested to be involved in IIP pathogenesis.