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Moving beyond genetics: is FAM13A a major biological contributor in lung physiology and chronic lung diseases?
  1. Harriet Corvol1,2,3,
  2. Craig A Hodges4,5,
  3. Mitchell L Drumm4,5,
  4. Loïc Guillot1,2
  1. 1INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France
  2. 2Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France
  3. 3Pneumologie pédiatrique, APHP, Hôpital Trousseau, Paris, France
  4. 4Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA
  5. 5Department of Genetics and Genome Sciences, Case Western University, Cleveland, Ohio, USA
  1. Correspondence to Dr L Guillot, Inserm UMR_S 938, CDR Saint Antoine, Inserm, Bât. Kourilsky 2ème Étage, 34 Rue Crozatier, 75012 Paris, France; loic.guillot{at}


Variants in FAM13A have been found in genome-wide association studies (GWAS) to associate with lung function in the general population as well as in several common chronic lung diseases (CLD) such as chronic obstructive pulmonary disease (COPD), asthma, as well as in idiopathic interstitial pneumonias (IIP). The gene was cloned in 2004, yet the encoded protein has not been characterised and its function is unknown. The redundancy of its genetic contribution in CLD suggests a major function of this gene both in lung physiology and CLD. This review provides a brief summary of the current knowledge of FAM13A, and demonstrates the necessity to resolve its biological function besides its well accepted genetic contribution. Further interpretations of FAM13A variants may help in the understanding of CLD mechanisms and reveal opportunity for intervention.

  • Respiratory Medicine
  • Genetics

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Lung diseases are a major cause of morbidity and mortality. Five global respiratory conditions, chronic obstructive pulmonary disease (COPD), asthma, lung cancer, acute respiratory infections and tuberculosis (TB), have been highlighted to largely contribute to the overall respiratory disease burden.1 Besides evidence of external causes (tobacco, household and outdoor pollution, and occupational exposures to lung toxins), these complex diseases are known to have a genetic contribution. Lung function is a heritable trait2–4 reflecting the physiological state of the lungs, and is mainly evaluated by measuring the forced expiratory volume in 1 s (FEV1) and/or the ratio (airway obstruction) FEV1/FVC (forced vital capacity) by spirometry. Interestingly, several genetic studies have identified that FAM13A is associated with lung function in the general population, as well as in three out of these five major lung diseases responsible of the overall burden of lung diseases, suggesting a major contributor of the lung physiology.

FAM13A cloning and genetic studies

Gene characteristics

FAM13A (family with sequence similarity 13, member A; MIM 613299), also known as FAM13A1, KIAA0914, and ARGHAP48, was cloned 10 years ago.5 This gene, localised on chromosome 4q22, was originally found in cattle near a quantitative trait locus (QTL) affecting milk production. Two splice variants have been identified in humans, named FAM13A isoform 1 (long variant) and isoform 2 (short variant) (formerly called FAM13A1_v2 and_v1, respectively). FAM13A isoform 2 diverges from isoform 1 in the 5′ UTR, lacks a portion of the 5′ coding region, and initiates translation at an alternate start codon.

FAM13A isoform 1 (NM_014883.3), used as the reference transcript, is thought to be the less abundant of the two. It is composed of 24 exons and is expected to encode a protein of 117 kDa. Northern blot data have shown high expression in the kidney, pancreas, liver, lung and thymus.5 In the protein sequence, FAM13A isoform 1 has a Rho (Ras homologous) GAP (GTPase-activating protein) domain suggesting a possible role in Rho GTPase signalling pathways (see The RhoGAP function hypothesis section). FAM13A isoform 2 (NM_001015045.2), composed of 17 exons, is more abundant and encodes a ubiquitous protein of 80 kDa, mainly expressed in skeletal muscles, thymus, brain and lungs. To date, 23 transcripts for FAM13A have been predicted ( including three other protein coding transcripts (table 1), however, with no biochemical or biological confirmation so far.

Table 1

FAM13A transcripts and protein Ids

FAM13A genotype/phenotype data

FAM13A was first found to associate with lung function in a genome-wide association study (GWAS) of the general population.6 Its contribution to lung function has also been assessed in the two paediatric cohorts, Prevention and Incidence of Asthma and Mite Allergy birth Cohort (PIAMA) and BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm Epidemiology).7 ,8 Using a candidate gene strategy (where previously associated SNPs with COPD were selected), one FAM13A variant (rs7671167) was shown to be associated with lung function (FEV1 and FVC) in the PIAMA Cohort. This association, however, was not replicated in the GWAS of the BAMSE children cohort, perhaps because of insufficient power due to the small size of the cohort (patients, n=389).

Further, FAM13A variants have been associated with lung function in several chronic lung diseases (CLD) such as COPD,919 asthma,20 ,21 and idiopathic interstitial pneumonias (IIP) (table 2).22 The variants that have been identified so far were in an intronic region of FAM13A, with no predicted functional effects by in silico analysis. However, in COPD, the association of this gene with lung function has been replicated in several studies with independent cohorts, suggesting a real contribution to the lung phenotype (table 2). As usually found in most GWAS the effect on heritability of one individual common SNP in one gene, such as FAM13A, is small. However, in a complex disease, such as COPD, the cumulative effect of several risk variants may increase the risk score.11 Also, even if these individual SNPs for FAM13A explain a small fraction of heritability, this GWAS detection may be important for the lung physiopathology. In fact, other studies on this causal gene may highlight its importance with experimental disruption (eg, Knockout mice) or detection of rare deleterious mutation.

Table 2

Genetic studies of FAM13A

Also, analysis of lung expression QTL (eQTL) with 409 lung/blood samples supports FAM13A as a causal COPD gene.23 Furthermore, in COPD patients, it has also been shown to be associated with lung volume and emphysema analysed by chest CT scans.24 Understanding how FAM13A influences severity of lung diseases is challenging, especially in a complex disease, such as COPD. Interestingly, using a phenotypic network analysis, it was recently shown that FAM13A (rs7161167) may lead to reduced FEV1 through mechanisms other than increased emphysema.25 This network analysis allows finding novel relationships between phenotypes and may provide some new strategy for basic science to reveal the role of this gene.

These variants may alter FAM13A function by changing RNA splicing, transcription efficiency, protein processing or function. However, absence of biochemical, cellular and functional data on FAM13A prevents future investigations to assess the functional biological consequences of the variants.

FAM13A biological data

Tissue and cell expression

Besides the first description of FAM13A by Cohen et al, only a few studies have investigated FAM13A expression in cells/tissues from various organs, and mostly by microarrays (table 3), and without deep biomolecular (transcripts pattern), biochemical (protein pattern) or cellular characterisation (cellular localisation).

Table 3

Biological expression studies of FAM13A

Moreover, in these studies, FAM13A function, that is, the cellular pathways associated, were not investigated. Interestingly, microarrays performed on cystic fibrosis (CF) primary nasal cells have suggested that FAM13A expression was higher in cells from patients with severe lung disease compared with cells from patients with a mild lung disease.27 However, these data were not further confirmed by other techniques (such as qPCR) or validated at the protein level. Analysis of lung samples from patients with IIP and controls has shown no difference in FAM13A mRNA expression by qPCR.22 FAM13A pattern of expression has not been extensively assessed in other CLD so far.

The role of this gene may be rapidly resolved thanks to the Knockout Mouse Project (KOMP) ( Indeed, Fam13a-deficient mice are now commercially available, making various strategies feasible to examine the contribution of FAM13A in the lung physiology and in physiopathological models. Classical knock-down, or conditional (promoter driven) knock-down by Cre recombination, will be possible in these animals, allowing one to examine the role of the protein specifically in the lung using cell-specific promoters (CC-10, SP-C, AQP5).32

The RhoGAP function hypothesis

As previously mentioned, FAM13A isoform 1 protein has a Rho GAP domain (amino acids: 43–231) suggesting its involvement in Rho GTPases (GTP phosphatase) activity modulation. In the human genome, as many as 70 proteins are predicted to contain this RhoGAP domain. Rho GTPases are key regulators of cytoskeletal dynamics and are involved in several cellular processes.

Rho GTPases cycle between an active and an inactive GDP-bound protein.33 RhoGAPs enhance intrinsic GTPase activity, leading to their inactive state. Regulation of Rho GTPase activity also involves GEFs (guanine nucleotide exchange factors), which activate Rho GTPases and GDIs (guanine nucleotide-dissociation inhibitors) that sequester the Rho GTPase at an inactive state in the cytosol (figure 1).

Figure 1

RhoGTPases cycling. GEFs (guanine nucleotide exchange factors); GDIs (guanine nucleotide-dissociation inhibitors); GAPs (GTPase-activating proteins).

In the lung, Rho GTPases are involved in the pulmonary endothelial barrier function,34 and have been shown to be dysregulated in several lung diseases, such as asthma, COPD and Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). A RhoGAP function of FAM13A makes it conceivable that genetic variation of FAM13A may affect Rho GTPases activity and associated cellular pathways, such as the endothelial barrier function, and contribute to inefficient gas exchanges, which are common in CLD. Interestingly, several modulators of Rho GTPases in immune cell migration and inflammation have been developed, especially for cancers,35 that will be helpful for CLD where the inflammatory and/or the immune response are impaired. Thus, assessing the role of FAM13A as a regulator of Rho GTPases may reveal new therapeutic options for CLD.


Although expected to be involved in the regulation of Rho GTPases, and despite its well accepted genetic contribution in several CLD, FAM13A biological functions are still unknown. In-depth in vitro and in vivo characterisations that apply in lung cells and available animal models, respectively, are now required. Defining FAM13A functions will further facilitate development of new CLD therapeutic strategies.



  • Contributors LG, HC drafted the manuscript; MLD and CAH critically revised it.

  • Funding LG received a grant from the French cystic-fibrosis non-profit organization Vaincre la mucoviscidose, a Legs Poix grant from the publicly funded source Chancellerie des Universités de Paris.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.