* 617538

ELONGATION FACTOR-LIKE GTPase 1; EFL1


Alternative titles; symbols

RIBOSOME ASSEMBLY 1 HOMOLOG; RIA1
ELONGATION FACTOR Tu GTP-BINDING DOMAIN-CONTAINING 1; EFTUD1
FAM42A


HGNC Approved Gene Symbol: EFL1

Cytogenetic location: 15q25.2     Genomic coordinates (GRCh38): 15:82,130,233-82,262,734 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q25.2 Shwachman-Diamond syndrome 2 617941 AR 3

TEXT

Description

EFL1 is a GTPase that acts in concert with SBDS (607444) in the cytoplasmic maturation of the 60S ribosomal subunit by catalyzing GTP-dependent removal of the assembly factor EIF6 (602912) from the maturing ribosome (Finch et al., 2011).


Cloning and Expression

By searching for the human ortholog of yeast Efl1, Finch et al. (2011) identified EFL1. The deduced 1,120-amino acid protein has 5 conserved GTPase motifs, including the GTP-binding G domain. By Western blot analysis of glioma tissues and cell lines, Saito et al. (2014) found that EFTUD1 had an apparent molecular mass of 125 kD. Immunohistochemical analysis revealed predominant EFTUD1 expression in the cytoplasm, with little expression in the nucleus.


Mapping

Hartz (2017) mapped the EFL1 gene to chromosome 15q25.2 based on an alignment of the EFL1 sequence (GenBank AK023181) with the genomic sequence (GRCh38).


Gene Function

Finch et al. (2011) showed that GTP and recombinant human SBDS and EFL1 cooperated to trigger release of human EIF6 (602912) from pre60S ribosomes isolated from Sbds-deficient mouse livers. EFL1 and SBDS independently and noncooperatively bound to the 60S subunit in vitro. The 60S subunit activated the GTPase activity of EFL1, but SBDS was required to stimulate EIF6 release. Two SBDS mutants with different SDS-associated missense mutations varied in their ability to enhance 60S-dependent GTPase activity of EFL1, but neither triggered EIF6 release. Finch et al. (2011) concluded that SBDS and EFL1 catalyze translational activation and proposed that SDS is a ribosomopathy caused by uncoupling GTP hydrolysis from EIF6 release.

Using quantitative PCR and Western blot analysis, Saito et al. (2014) found that expression of EFTUD1 mRNA and protein was upregulated in glioma tissues and cell lines compared with normal brain tissue. Knockdown of EFTUD1 in glioma cell lines via short interfering RNA caused G1 cell cycle arrest, apoptosis, and autophagy, as well as reduced cell proliferation. The ribosome biogenesis factor EIF6, which normally was detected in the nucleus, redistributed to the perinuclear regions and cytoplasm in the absence of EFTUD1. Saito et al. (2014) concluded that the cellular effects of EFTUD1 knockdown were due to impaired ribosome biogenesis.

Garcia-Marquez et al. (2015) determined that binding of EFL1 to both GDP and GTP is a 2-step process with an initial binding event followed by a conformational change. The affinity of EFL1 for GTP was 10-fold lower than that calculated for GDP. Association of EFL1 with SBDS did not alter the affinity of EFL1 for GTP, but significantly reduced its dissociation constant for GDP. Thus, SBDS acted as a guanine nucleotide exchange factor (GEF) for EFL1, promoting activation of EFL1 by release of GDP. Garcia-Marquez et al. (2015) concluded that SBDS couples the energy liberated from the hydrolysis of GTP by EFL1 for release of EIF6 from the surface of the 60S ribosomal subunit. They further found that SBDS mutations found in patients with Shwachman-Diamond syndrome (SDS; 260400) disrupted the interaction of SBDS with EFL1 and prevented SBDS regulation of the affinity of EFL1 toward guanine nucleotides.


Molecular Genetics

In 6 affected children from 3 unrelated families with Shwachman-Diamond syndrome (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for missense mutations in the EFL1 gene: 2 Mexican sibs were homozygous for an M882K substitution (617538.0001), and 4 Palestinian Muslim children were homozygous for an R1095Q substitution (617538.0002). Functional analysis demonstrated that the mutations impair eIF6 release from the 60s ribosomal subunit.

Tan et al. (2018) identified a homozygous mutation in the EFL1 gene (617538.0003) in a 14-year-old girl with SDS2. The mutation, which was identified by trio whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.

By whole-exome sequencing followed by Sanger sequencing, Tan et al. (2019) identified mutations in the EFL1 gene in 3 patients with SDS2. Compound heterozygous mutations (617538.0004-617538.0005) were identified in patient 1, a homozygous mutation (617538.0006) was identified in patient 2, and a single heterozygous mutation (617538.0007) inherited from the father was identified in patient 3. There was near absence of detectable mRNA transcripts from the maternal allele in patient 3, suggesting a noncoding mutation in the maternal allele affecting EFL1 expression. Tan et al. (2019) demonstrated that the EFL1 mutations resulted in impaired eIF6 release from the late 60S cytoplasmic subunit, causing defective ribosomal subunit joining and reduced global protein synthesis.

In 3 Korean patients with SDS2, Lee et al. (2021) identified compound heterozygous mutations in the EIF1 gene (617535.0008-617535.0010); one of the mutations (T1069A; 617538.0008) occurred in all 3. All 3 patients also had somatic partial loss of heterozygosity (LOH) of chromosome 15, including the EIF1 gene, in bone marrow-derived cells, resulting in homozygosity for the T1069A allele in some cells. In patients I-1 and III-1, this loss of heterozygosity was not observed in non-bone marrow-derived cells. Lee et al. (2021) concluded that the LOH on chromosome 15 and homozygosity for a relatively milder mutation resulted in avoidance of catastrophic consequences. EFL1 -/- HeLa cells exhibited a partial rescue of ribosome assembly when transfected with EFL1 with the T1069A mutation, suggesting that this mutation is hypomorphic.


Animal Model

Tan et al. (2019) studied a mouse model with homozygosity for a K983R mutation in the Efl1 gene. The mice had decreased bone density, decreased weight due to a progressive loss of fat mass accumulation, and decreased bone marrow cellularity. Some of the mutant mice also had gait and memory abnormalities. Functional studies demonstrated an increased 60S:80S ribosomal subunit ratio in mouse embryonic fibroblasts from affected mice, indicating a defect in ribosomal maturation.

Lee et al. (2021) generated mice that had a homozygous knockout for Efl1 and a homozygous knock-in for a T1076A mutation (orthologous to the human T1069A mutation) in the Efl1 gene. The knockout mice had embryonic lethality, whereas the knock-in T1076A mice survived to birth. After birth, knock-in mice were smaller than wildtype mice and died early. They exhibited bone marrow deficiency, including reduced hemoglobin, white blood cells, and platelets. Livers of the knock-in mice had a lower 80S ribosome peak compared to livers from wildtype mice.

Lee et al. (2021) studied a morpholino-targeted zebrafish model of efl1 deficiency. The morphant fish had smaller heads and eyes and impaired hematopoiesis. The phenotypes were rescued by introduction of wildtype Efl1 mRNA and partially rescued by introduction of Efl1 with the T1069A mutation (617538.0008).


ALLELIC VARIANTS ( 10 Selected Examples):

.0001 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, MET882LYS
  
RCV000625721

In a Mexican brother and sister with Shwachman-Diamond syndrome-2 (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for a c.2645T-A transversion (c.2645T-A, NM_024580.5) in exon 18 of the EFL1 gene, resulting in a met882-to-lys (M882K) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in the ExAC database. Functional analysis in yeast cells showed that the M992K mutant cannot release eIF6 (602912) from the surface of the 60S ribosomal subunit.


.0002 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG1095GLN
  
RCV000625722...

In 3 affected sibs and an unrelated affected girl from Palestinian Muslim families with Shwachman-Diamond syndrome-2 (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for a c.3284G-A transition (c.3284G-A, NM_024580.5) in the EFL1 gene, resulting in an arg1095-to-gln (R1095Q) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in approximately 940 Muslim Arab in-house exomes; however, the variant was present in 2 of 60,700 exomes in the ExAC database. Functional analysis in yeast cells showed that the R1095Q mutant cannot release eIF6 (602912) from the surface of the 60S ribosomal subunit.


.0003 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, THR127ALA
  
RCV000625990

In a 14-year-old girl with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2018) identified homozygosity for a c.379A-G transition (c.379A-G, NM_024580.5) in the EFL1 gene, resulting in a thr127-to-ala (T127A) substitution at a conserved site. The mutation was identified by trio whole-exome sequencing and was present in the carrier state in the parents. The mutation was absent from an internal database of 13,119 samples and from the EVS and ExAC databases. The mutation was present in 1 of 240,260 alleles in the gnomAD database.


.0004 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG754TER
  
RCV002248311

In a patient (P1) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified compound heterozygous mutations in the EFL1 gene: a c.2260C-T transition, resulting in an arg754-to-ter (R754X) substitution, and a c.1514T-C transition, resulting in a phe505-to-ser (F505S; 617538.0005) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents and an unaffected sib. cDNA sequencing in the patient suggested reduction in the amount of transcript with the R754X mutation, indicating that the mutation resulted in partial nonsense-mediated decay. Immunoblot analysis in patient fibroblasts showed reduction of EFL1 protein expression compared to controls. Tan et al. (2019) also demonstrated that the mutations resulted in a defect in ribosomal subunit joining and a reduction in total protein synthesis in patient fibroblasts.


.0005 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, PHE505SER
  
RCV002248312

For discussion of the c.1514T-C transition in the EFL1 gene, resulting in a phe505-to-ser (F505S) substitution, that was identified in compound heterozygous state in a patient with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Tan et al. (2019), see 617538.0004.


.0006 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG970HIS
  
RCV001265750...

In a patient (P2) from Guinea, born to consanguineous parents, with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified a homozygous c.2908C-T transition in the EFL1 gene, resulting in an arg970-to-his (R970H) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was found in the carrier state in the parents and 3 unaffected sibs. Tan et al. (2019) also demonstrated that the mutations resulted in an increased 60S:80S ribosomal subunit ratio and a reduction in total protein synthesis in patient fibroblasts.


.0007 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, CYS883GLY
  
RCV002248313

In a patient (P3) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified heterozygosity for a c.2647T-G transversion in the EFL1 gene, resulting in a cys883-to-gly (C883G) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was found in the carrier state in the father and an unaffected sib. A second mutation was not identified; however, there was near absence of detectable mRNA transcripts from the maternal allele, suggesting a noncoding mutation in the maternal allele affecting EFL1 expression. Immunoblot analysis in patient lymphoblastoid cell lines demonstrated reduced EFL1 protein expression. Tan et al. (2019) also demonstrated that the mutation resulted in a defect in ribosomal subunit joining and a reduction in total protein synthesis in patient fibroblasts.


.0008 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, THR1069ALA
  
RCV002248314

In a Korean patient (patient I-1) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Lee et al. (2021) identified compound heterozygous mutations in the EFL1 gene: a c.3205A-G transition (c.3205A-G, NM_024580.5), resulting in a thr1069-to-ala (T1069A) substitution, and a 1-bp duplication (c.2478dupT; 617538.0009), resulting in a frameshift and premature termination (Gly827TrpfsTer13). The mutations were identified by whole-exome sequencing and the parents were shown to be mutation carriers. The T1069A mutation was present in the gnomAD database at a frequency of 3/17972 and the c.2478dupT mutation was not present in the gnomAD database. In the patient, the c.2478dupT mutation was present at an allele frequency of 8.3% based on the whole-exome sequencing in blood and a frequency of 15% based on amplicon sequencing in blood and bone marrow but a frequency of 50% in most other tissues. Lee et al. (2021) determined that there was a copy neutral, somatic partial loss of heterozygosity including the EFL1 locus, resulting in homozygosity for the maternally inherited T1069A mutation, that was restricted to the bone marrow. EFL1-/- HeLa cells exhibited a partial rescue of ribosome assembly when transfected with EFL1 with the T1069A mutation, suggesting that this mutation is hypomorphic.

In 2 unrelated Korean patients (patients II-1 and III-1) with SDS2, Lee et al. (2021) identified compound heterozygous mutations in the EFL1 gene: T1069A and a c.89A-G transition, resulting in a his30-to-arg (H30R; 617538.0010) substitution. The mutations were identified by whole-exome sequencing. The H30R mutation was present in the gnomAD database at a frequency of 5.1 x 10(-5). In patients II-1 and III-1, the H30R mutation was present at an allele frequency of 14.8% and 36.8%, respectively, based on the whole-exome sequencing in blood. Both patients had a copy neutral, somatic partial loss of heterozygosity including the EFL1 locus, resulting in partial homozygosity for the T1069A mutation. Amplicon sequencing in buccal cells from patient III-1 demonstrated an allele frequency of 52.5% for the T1069A mutation and 47.3% for the H30R mutation.


.0009 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, 1-BP DUP, 2478T
  
RCV002248315

For discussion of the 1-bp duplication (c.2478dupT, NM_024580.5) in the EFL1 gene, resulting in a frameshift and premature termination (Gly827fsTer13), that was identified in compound heterozygous state in a patient with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Lee et al. (2021), see 617538.0008.


.0010 SHWACHMAN-DIAMOND SYNDROME 2

EFL1, HIS30ARG
  
RCV002248316

For discussion of the c.89A-G transition (c.89A-G, NM_024580.5) in the EFL1 gene, resulting in a his30-to-arg (H30R) substitution, that was identified in compound heterozygous state in 2 patients with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Lee et al. (2021), see 617538.0008.


REFERENCES

  1. Finch, A. J., Hilcenko, C., Basse, N., Drynan, L. F., Goyenechea, B., Menne, T. F., Gonzalez Fernandez, A., Simpson, P., D'Santos, C. S., Arends, M. J., Donadieu, J., Bellanne-Chantelot, C., Costanzo, M., Boone, C., McKenzie, A. N., Freund, S. M. V., Warren, A. J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 25: 917-929, 2011. [PubMed: 21536732, images, related citations] [Full Text]

  2. Garcia-Marquez, A., Gijsbers, A., de la Mora, E., Sanchez-Puig, N. Defective guanine nucleotide exchange in the elongation factor-like 1 (EFL1) GTPase by mutations in the Shwachman-Diamond syndrome protein. J. Biol. Chem. 290: 17669-17678, 2015. [PubMed: 25991726, images, related citations] [Full Text]

  3. Hartz, P. A. Personal Communication. Baltimore, Md. June 6, 2017.

  4. Lee, S., Shin, C. H., Lee, J., Jeong, S. D., Hong, C. R., Kim, J.-D., Kim, A.-R., Pak, B., Son, S. J., Kokhan, O., Yoo, T., Ko, J. S., and 10 others. Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome. Blood 138: 2117-2128, 2021. Note: Erratum: Blood 142: 857 only, 2023. [PubMed: 34115847, related citations] [Full Text]

  5. Saito, K., Iizuka, Y., Ohta, S., Takahashi, S., Nakamura, K., Saya, H., Yoshida, K., Kawakami, Y., Toda, M. Functional analysis of a novel glioma antigen, EFTUD1. Neuro-Oncol. 16: 1618-1629, 2014. [PubMed: 25015090, images, related citations] [Full Text]

  6. Stepensky, P., Chacon-Flores, M., Kim, K. H., Aburzaitoun, O., Bautista-Santos, A., Simanovsky, N., Siliqi, D., Altamura, D., Mendez-Godoy, A., Gijsbers, A., Eddin, A. N., Dor, T., Charrow, J., Sanchez-Puig, N., Elpeleg, O. Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J. Med. Genet. 54: 558-566, 2017. [PubMed: 28331068, related citations] [Full Text]

  7. Tan, Q. K.-G., Cope, H., Spillmann, R. C., Strong, N., Jiang, Y.-H., McDonald, M. T., Rothman, J. A., Butler, M. W., Frush, D. P., Lachman, R. S., Lee, B., Bacino, C. A., Bonner, M. J., McCall, C. M., Pendse, A. A., Walley, N., Undiagnosed Diseases Network, Shashi, V., Pena, L. D. M. Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features. Cold Spring Harbor Molec. Case Stud. 4: a003046, 2018. [PubMed: 29970384, images, related citations] [Full Text]

  8. Tan, S., Kermasson, L., Hoslin, A., Jaako, P., Faille, A., Acevedo-Arozena, A., Lengline, E., Ranta, D., Poiree, M., Fenneteau, O., Ducou le Pointe, H., Fumagalli, S., and 9 others. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome. Blood 134: 277-290, 2019. [PubMed: 31151987, images, related citations] [Full Text]


Hilary J. Vernon - updated : 04/15/2022
Marla J. F. O'Neill - updated : 04/19/2018
Creation Date:
Patricia A. Hartz : 06/19/2017
alopez : 01/29/2024
carol : 04/18/2022
carol : 04/15/2022
carol : 04/19/2018
carol : 06/19/2017

* 617538

ELONGATION FACTOR-LIKE GTPase 1; EFL1


Alternative titles; symbols

RIBOSOME ASSEMBLY 1 HOMOLOG; RIA1
ELONGATION FACTOR Tu GTP-BINDING DOMAIN-CONTAINING 1; EFTUD1
FAM42A


HGNC Approved Gene Symbol: EFL1

Cytogenetic location: 15q25.2     Genomic coordinates (GRCh38): 15:82,130,233-82,262,734 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q25.2 Shwachman-Diamond syndrome 2 617941 Autosomal recessive 3

TEXT

Description

EFL1 is a GTPase that acts in concert with SBDS (607444) in the cytoplasmic maturation of the 60S ribosomal subunit by catalyzing GTP-dependent removal of the assembly factor EIF6 (602912) from the maturing ribosome (Finch et al., 2011).


Cloning and Expression

By searching for the human ortholog of yeast Efl1, Finch et al. (2011) identified EFL1. The deduced 1,120-amino acid protein has 5 conserved GTPase motifs, including the GTP-binding G domain. By Western blot analysis of glioma tissues and cell lines, Saito et al. (2014) found that EFTUD1 had an apparent molecular mass of 125 kD. Immunohistochemical analysis revealed predominant EFTUD1 expression in the cytoplasm, with little expression in the nucleus.


Mapping

Hartz (2017) mapped the EFL1 gene to chromosome 15q25.2 based on an alignment of the EFL1 sequence (GenBank AK023181) with the genomic sequence (GRCh38).


Gene Function

Finch et al. (2011) showed that GTP and recombinant human SBDS and EFL1 cooperated to trigger release of human EIF6 (602912) from pre60S ribosomes isolated from Sbds-deficient mouse livers. EFL1 and SBDS independently and noncooperatively bound to the 60S subunit in vitro. The 60S subunit activated the GTPase activity of EFL1, but SBDS was required to stimulate EIF6 release. Two SBDS mutants with different SDS-associated missense mutations varied in their ability to enhance 60S-dependent GTPase activity of EFL1, but neither triggered EIF6 release. Finch et al. (2011) concluded that SBDS and EFL1 catalyze translational activation and proposed that SDS is a ribosomopathy caused by uncoupling GTP hydrolysis from EIF6 release.

Using quantitative PCR and Western blot analysis, Saito et al. (2014) found that expression of EFTUD1 mRNA and protein was upregulated in glioma tissues and cell lines compared with normal brain tissue. Knockdown of EFTUD1 in glioma cell lines via short interfering RNA caused G1 cell cycle arrest, apoptosis, and autophagy, as well as reduced cell proliferation. The ribosome biogenesis factor EIF6, which normally was detected in the nucleus, redistributed to the perinuclear regions and cytoplasm in the absence of EFTUD1. Saito et al. (2014) concluded that the cellular effects of EFTUD1 knockdown were due to impaired ribosome biogenesis.

Garcia-Marquez et al. (2015) determined that binding of EFL1 to both GDP and GTP is a 2-step process with an initial binding event followed by a conformational change. The affinity of EFL1 for GTP was 10-fold lower than that calculated for GDP. Association of EFL1 with SBDS did not alter the affinity of EFL1 for GTP, but significantly reduced its dissociation constant for GDP. Thus, SBDS acted as a guanine nucleotide exchange factor (GEF) for EFL1, promoting activation of EFL1 by release of GDP. Garcia-Marquez et al. (2015) concluded that SBDS couples the energy liberated from the hydrolysis of GTP by EFL1 for release of EIF6 from the surface of the 60S ribosomal subunit. They further found that SBDS mutations found in patients with Shwachman-Diamond syndrome (SDS; 260400) disrupted the interaction of SBDS with EFL1 and prevented SBDS regulation of the affinity of EFL1 toward guanine nucleotides.


Molecular Genetics

In 6 affected children from 3 unrelated families with Shwachman-Diamond syndrome (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for missense mutations in the EFL1 gene: 2 Mexican sibs were homozygous for an M882K substitution (617538.0001), and 4 Palestinian Muslim children were homozygous for an R1095Q substitution (617538.0002). Functional analysis demonstrated that the mutations impair eIF6 release from the 60s ribosomal subunit.

Tan et al. (2018) identified a homozygous mutation in the EFL1 gene (617538.0003) in a 14-year-old girl with SDS2. The mutation, which was identified by trio whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.

By whole-exome sequencing followed by Sanger sequencing, Tan et al. (2019) identified mutations in the EFL1 gene in 3 patients with SDS2. Compound heterozygous mutations (617538.0004-617538.0005) were identified in patient 1, a homozygous mutation (617538.0006) was identified in patient 2, and a single heterozygous mutation (617538.0007) inherited from the father was identified in patient 3. There was near absence of detectable mRNA transcripts from the maternal allele in patient 3, suggesting a noncoding mutation in the maternal allele affecting EFL1 expression. Tan et al. (2019) demonstrated that the EFL1 mutations resulted in impaired eIF6 release from the late 60S cytoplasmic subunit, causing defective ribosomal subunit joining and reduced global protein synthesis.

In 3 Korean patients with SDS2, Lee et al. (2021) identified compound heterozygous mutations in the EIF1 gene (617535.0008-617535.0010); one of the mutations (T1069A; 617538.0008) occurred in all 3. All 3 patients also had somatic partial loss of heterozygosity (LOH) of chromosome 15, including the EIF1 gene, in bone marrow-derived cells, resulting in homozygosity for the T1069A allele in some cells. In patients I-1 and III-1, this loss of heterozygosity was not observed in non-bone marrow-derived cells. Lee et al. (2021) concluded that the LOH on chromosome 15 and homozygosity for a relatively milder mutation resulted in avoidance of catastrophic consequences. EFL1 -/- HeLa cells exhibited a partial rescue of ribosome assembly when transfected with EFL1 with the T1069A mutation, suggesting that this mutation is hypomorphic.


Animal Model

Tan et al. (2019) studied a mouse model with homozygosity for a K983R mutation in the Efl1 gene. The mice had decreased bone density, decreased weight due to a progressive loss of fat mass accumulation, and decreased bone marrow cellularity. Some of the mutant mice also had gait and memory abnormalities. Functional studies demonstrated an increased 60S:80S ribosomal subunit ratio in mouse embryonic fibroblasts from affected mice, indicating a defect in ribosomal maturation.

Lee et al. (2021) generated mice that had a homozygous knockout for Efl1 and a homozygous knock-in for a T1076A mutation (orthologous to the human T1069A mutation) in the Efl1 gene. The knockout mice had embryonic lethality, whereas the knock-in T1076A mice survived to birth. After birth, knock-in mice were smaller than wildtype mice and died early. They exhibited bone marrow deficiency, including reduced hemoglobin, white blood cells, and platelets. Livers of the knock-in mice had a lower 80S ribosome peak compared to livers from wildtype mice.

Lee et al. (2021) studied a morpholino-targeted zebrafish model of efl1 deficiency. The morphant fish had smaller heads and eyes and impaired hematopoiesis. The phenotypes were rescued by introduction of wildtype Efl1 mRNA and partially rescued by introduction of Efl1 with the T1069A mutation (617538.0008).


ALLELIC VARIANTS 10 Selected Examples):

.0001   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, MET882LYS
SNP: rs1316615934, gnomAD: rs1316615934, ClinVar: RCV000625721

In a Mexican brother and sister with Shwachman-Diamond syndrome-2 (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for a c.2645T-A transversion (c.2645T-A, NM_024580.5) in exon 18 of the EFL1 gene, resulting in a met882-to-lys (M882K) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in the ExAC database. Functional analysis in yeast cells showed that the M992K mutant cannot release eIF6 (602912) from the surface of the 60S ribosomal subunit.


.0002   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG1095GLN
SNP: rs376095522, gnomAD: rs376095522, ClinVar: RCV000625722, RCV003558479

In 3 affected sibs and an unrelated affected girl from Palestinian Muslim families with Shwachman-Diamond syndrome-2 (SDS2; 617941), Stepensky et al. (2017) identified homozygosity for a c.3284G-A transition (c.3284G-A, NM_024580.5) in the EFL1 gene, resulting in an arg1095-to-gln (R1095Q) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in approximately 940 Muslim Arab in-house exomes; however, the variant was present in 2 of 60,700 exomes in the ExAC database. Functional analysis in yeast cells showed that the R1095Q mutant cannot release eIF6 (602912) from the surface of the 60S ribosomal subunit.


.0003   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, THR127ALA
SNP: rs1441937959, gnomAD: rs1441937959, ClinVar: RCV000625990

In a 14-year-old girl with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2018) identified homozygosity for a c.379A-G transition (c.379A-G, NM_024580.5) in the EFL1 gene, resulting in a thr127-to-ala (T127A) substitution at a conserved site. The mutation was identified by trio whole-exome sequencing and was present in the carrier state in the parents. The mutation was absent from an internal database of 13,119 samples and from the EVS and ExAC databases. The mutation was present in 1 of 240,260 alleles in the gnomAD database.


.0004   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG754TER
SNP: rs1330065864, gnomAD: rs1330065864, ClinVar: RCV002248311

In a patient (P1) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified compound heterozygous mutations in the EFL1 gene: a c.2260C-T transition, resulting in an arg754-to-ter (R754X) substitution, and a c.1514T-C transition, resulting in a phe505-to-ser (F505S; 617538.0005) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents and an unaffected sib. cDNA sequencing in the patient suggested reduction in the amount of transcript with the R754X mutation, indicating that the mutation resulted in partial nonsense-mediated decay. Immunoblot analysis in patient fibroblasts showed reduction of EFL1 protein expression compared to controls. Tan et al. (2019) also demonstrated that the mutations resulted in a defect in ribosomal subunit joining and a reduction in total protein synthesis in patient fibroblasts.


.0005   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, PHE505SER
SNP: rs763132789, gnomAD: rs763132789, ClinVar: RCV002248312

For discussion of the c.1514T-C transition in the EFL1 gene, resulting in a phe505-to-ser (F505S) substitution, that was identified in compound heterozygous state in a patient with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Tan et al. (2019), see 617538.0004.


.0006   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, ARG970HIS
SNP: rs757808847, gnomAD: rs757808847, ClinVar: RCV001265750, RCV001880096, RCV002251569

In a patient (P2) from Guinea, born to consanguineous parents, with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified a homozygous c.2908C-T transition in the EFL1 gene, resulting in an arg970-to-his (R970H) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was found in the carrier state in the parents and 3 unaffected sibs. Tan et al. (2019) also demonstrated that the mutations resulted in an increased 60S:80S ribosomal subunit ratio and a reduction in total protein synthesis in patient fibroblasts.


.0007   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, CYS883GLY
SNP: rs2141228362, ClinVar: RCV002248313

In a patient (P3) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Tan et al. (2019) identified heterozygosity for a c.2647T-G transversion in the EFL1 gene, resulting in a cys883-to-gly (C883G) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was found in the carrier state in the father and an unaffected sib. A second mutation was not identified; however, there was near absence of detectable mRNA transcripts from the maternal allele, suggesting a noncoding mutation in the maternal allele affecting EFL1 expression. Immunoblot analysis in patient lymphoblastoid cell lines demonstrated reduced EFL1 protein expression. Tan et al. (2019) also demonstrated that the mutation resulted in a defect in ribosomal subunit joining and a reduction in total protein synthesis in patient fibroblasts.


.0008   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, THR1069ALA
SNP: rs756494164, gnomAD: rs756494164, ClinVar: RCV002248314

In a Korean patient (patient I-1) with Shwachman-Diamond syndrome-2 (SDS2; 617941), Lee et al. (2021) identified compound heterozygous mutations in the EFL1 gene: a c.3205A-G transition (c.3205A-G, NM_024580.5), resulting in a thr1069-to-ala (T1069A) substitution, and a 1-bp duplication (c.2478dupT; 617538.0009), resulting in a frameshift and premature termination (Gly827TrpfsTer13). The mutations were identified by whole-exome sequencing and the parents were shown to be mutation carriers. The T1069A mutation was present in the gnomAD database at a frequency of 3/17972 and the c.2478dupT mutation was not present in the gnomAD database. In the patient, the c.2478dupT mutation was present at an allele frequency of 8.3% based on the whole-exome sequencing in blood and a frequency of 15% based on amplicon sequencing in blood and bone marrow but a frequency of 50% in most other tissues. Lee et al. (2021) determined that there was a copy neutral, somatic partial loss of heterozygosity including the EFL1 locus, resulting in homozygosity for the maternally inherited T1069A mutation, that was restricted to the bone marrow. EFL1-/- HeLa cells exhibited a partial rescue of ribosome assembly when transfected with EFL1 with the T1069A mutation, suggesting that this mutation is hypomorphic.

In 2 unrelated Korean patients (patients II-1 and III-1) with SDS2, Lee et al. (2021) identified compound heterozygous mutations in the EFL1 gene: T1069A and a c.89A-G transition, resulting in a his30-to-arg (H30R; 617538.0010) substitution. The mutations were identified by whole-exome sequencing. The H30R mutation was present in the gnomAD database at a frequency of 5.1 x 10(-5). In patients II-1 and III-1, the H30R mutation was present at an allele frequency of 14.8% and 36.8%, respectively, based on the whole-exome sequencing in blood. Both patients had a copy neutral, somatic partial loss of heterozygosity including the EFL1 locus, resulting in partial homozygosity for the T1069A mutation. Amplicon sequencing in buccal cells from patient III-1 demonstrated an allele frequency of 52.5% for the T1069A mutation and 47.3% for the H30R mutation.


.0009   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, 1-BP DUP, 2478T
SNP: rs1380341628, ClinVar: RCV002248315

For discussion of the 1-bp duplication (c.2478dupT, NM_024580.5) in the EFL1 gene, resulting in a frameshift and premature termination (Gly827fsTer13), that was identified in compound heterozygous state in a patient with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Lee et al. (2021), see 617538.0008.


.0010   SHWACHMAN-DIAMOND SYNDROME 2

EFL1, HIS30ARG
SNP: rs370108445, gnomAD: rs370108445, ClinVar: RCV002248316

For discussion of the c.89A-G transition (c.89A-G, NM_024580.5) in the EFL1 gene, resulting in a his30-to-arg (H30R) substitution, that was identified in compound heterozygous state in 2 patients with Shwachman-Diamond syndrome-2 (SDS2; 617941) by Lee et al. (2021), see 617538.0008.


REFERENCES

  1. Finch, A. J., Hilcenko, C., Basse, N., Drynan, L. F., Goyenechea, B., Menne, T. F., Gonzalez Fernandez, A., Simpson, P., D'Santos, C. S., Arends, M. J., Donadieu, J., Bellanne-Chantelot, C., Costanzo, M., Boone, C., McKenzie, A. N., Freund, S. M. V., Warren, A. J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 25: 917-929, 2011. [PubMed: 21536732] [Full Text: https://doi.org/10.1101/gad.623011]

  2. Garcia-Marquez, A., Gijsbers, A., de la Mora, E., Sanchez-Puig, N. Defective guanine nucleotide exchange in the elongation factor-like 1 (EFL1) GTPase by mutations in the Shwachman-Diamond syndrome protein. J. Biol. Chem. 290: 17669-17678, 2015. [PubMed: 25991726] [Full Text: https://doi.org/10.1074/jbc.M114.626275]

  3. Hartz, P. A. Personal Communication. Baltimore, Md. June 6, 2017.

  4. Lee, S., Shin, C. H., Lee, J., Jeong, S. D., Hong, C. R., Kim, J.-D., Kim, A.-R., Pak, B., Son, S. J., Kokhan, O., Yoo, T., Ko, J. S., and 10 others. Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome. Blood 138: 2117-2128, 2021. Note: Erratum: Blood 142: 857 only, 2023. [PubMed: 34115847] [Full Text: https://doi.org/10.1182/blood.2021010913]

  5. Saito, K., Iizuka, Y., Ohta, S., Takahashi, S., Nakamura, K., Saya, H., Yoshida, K., Kawakami, Y., Toda, M. Functional analysis of a novel glioma antigen, EFTUD1. Neuro-Oncol. 16: 1618-1629, 2014. [PubMed: 25015090] [Full Text: https://doi.org/10.1093/neuonc/nou132]

  6. Stepensky, P., Chacon-Flores, M., Kim, K. H., Aburzaitoun, O., Bautista-Santos, A., Simanovsky, N., Siliqi, D., Altamura, D., Mendez-Godoy, A., Gijsbers, A., Eddin, A. N., Dor, T., Charrow, J., Sanchez-Puig, N., Elpeleg, O. Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J. Med. Genet. 54: 558-566, 2017. [PubMed: 28331068] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104366]

  7. Tan, Q. K.-G., Cope, H., Spillmann, R. C., Strong, N., Jiang, Y.-H., McDonald, M. T., Rothman, J. A., Butler, M. W., Frush, D. P., Lachman, R. S., Lee, B., Bacino, C. A., Bonner, M. J., McCall, C. M., Pendse, A. A., Walley, N., Undiagnosed Diseases Network, Shashi, V., Pena, L. D. M. Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features. Cold Spring Harbor Molec. Case Stud. 4: a003046, 2018. [PubMed: 29970384] [Full Text: https://doi.org/10.1101/mcs.a003046]

  8. Tan, S., Kermasson, L., Hoslin, A., Jaako, P., Faille, A., Acevedo-Arozena, A., Lengline, E., Ranta, D., Poiree, M., Fenneteau, O., Ducou le Pointe, H., Fumagalli, S., and 9 others. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome. Blood 134: 277-290, 2019. [PubMed: 31151987] [Full Text: https://doi.org/10.1182/blood.2018893404]


Contributors:
Hilary J. Vernon - updated : 04/15/2022
Marla J. F. O'Neill - updated : 04/19/2018

Creation Date:
Patricia A. Hartz : 06/19/2017

Edit History:
alopez : 01/29/2024
carol : 04/18/2022
carol : 04/15/2022
carol : 04/19/2018
carol : 06/19/2017