ABCMdb

PMID: 25553246

Coghlan MA, Shifren A, Huang HJ, Russell TD, Mitra RD, Zhang Q, Wegner DJ, Cole FS, Hamvas A
Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations.
BMJ Open Respir Res. 2014 Dec 10;1(1):e000057. doi: 10.1136/bmjresp-2014-000057. eCollection 2014., [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCA3 p.Glu292Val No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. Login to comment 46 ABCA3 p.Glu292Val No individuals had single rare mutations in two different genes, although one individual was homozygous for ABCA3 p.E292V. Login to comment 69 ABCA3 p.Glu292Val ABCA3 p.Arg1474Trp Table 3 Mutations identified in IPF and COPD cohorts of European descent Gene Mutation Amino acid change IPF* (ED) (n=119) (n (MAF)) COPD (n=178) (n (MAF)) ESP (ED) (MAF), % p Value (IPF vs COPD) dbSNP number SFTPA2 c.532G>A V178M 1 (0.4%)ߤ 0 0.01 0.4 SFTPC c.218T>C I73T 3 (1.3%)ߤ 0 0 rs121917834 c.329T>G L110R 1 (0.4%) 0 0 c.334G>A A112T 1 (0.4%) 0 0 Collapsed frequency 2.1% 0.01 ABCA3 c.875A>T E292V 4 (1.68%) 3 (0.84%) 0.45 rs149989682 c.4420G>A R1474W 0 3 (0.84%) 0.36 rs146709251 Collapsed frequency 1.68% 1.68% 1.0 NKX2-1 0 0 NA TERT c.323G>C ߥR108P 1 (0.42%) 0 0 c.994C>T ߥL332F 1 (0.42%) 0 0 c.1775A>G ߥH592R 1 (0.42%)ߤ 0 0 c.2110C>T P704S 2 (0.84%) 0 0 rs199422297 Collapsed frequency 2.1% 0.01 *All individuals with mutations were of European descent. Login to comment 93 ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Asp123Asn ABCA3 p.Gly964Asp Homozygous recessive or compound heterozygous ABCA3 mutations cause neonatal respiratory failure and childhood ILD, and single ABCA3 mutations (p.E292V and p.D123N) interacting with SFTPC p.I73T have been reported in two families, one with childhood ILD and one with IPF.10 34 Our identification of one individual who was homozygous for ABCA3 p.E292V adds to the recent identification of a kindred with pulmonary fibrosis due to a p.G964D thus further supporting the possibility that adult-onset fibrotic lung disease due to homozygous or compound heterozygous mutations in ABCA3 may occur.11 In contrast to our previous study that demonstrated an enrichment of single ABCA3 mutations in newborns with RDS, suggesting a developmental interaction that increased risk or severity of disease, we did not find the frequency of single ABCA3 mutations in the IPF cohort to be greater than the 3-5% in the general population. Login to comment 94 ABCA3 p.Glu292Val This is consistent with a prior study showing single E292V mutations were not a major risk factor for pulmonary disease in the general population, and also suggests that interactions with other modifiers are less likely to increase risk for disease.35-37 Since mutations in NKX2-1 are extremely rare in the general population, the lack of identifiable mutations in NKX2-1 in our IPF and COPD cohorts may simply be a function of the limited sample size of our cohort, thus making it difficult to know the true prevalence of NKX2-1 mutations in patients with IPF. Login to comment