Alternative titles; symbols
HGNC Approved Gene Symbol: CSF1R
SNOMEDCT: 702427005; ICD10CM: G93.44;
Cytogenetic location: 5q32 Genomic coordinates (GRCh38) : 5:150,053,295-150,113,365 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Brain abnormalities, neurodegeneration, and dysosteosclerosis | 618476 | Autosomal recessive | 3 |
| Leukoencephalopathy, diffuse hereditary, with spheroids 1 | 221820 | Autosomal dominant | 3 |
The CSF1R gene, also known as c-FMS, encodes a tyrosine kinase growth factor receptor for colony-stimulating factor-1 (CSF1; 120420), the macrophage- and monocyte-specific growth factor (Ridge et al., 1990).
The CSF1R gene is expressed in mononuclear phagocytes in the brain, known as microglia, which play a role in neuronal and brain development (summary by Erblich et al., 2011), as well as in osteoclasts, which play an important role in bone mineralization (summary by Dai et al., 2004). Phosphorylation of CSF1R triggered by ligand binding to the receptor activates multiple downstream kinase pathways, including PI3K (see 171834), ERK1/2 (see 176948), and JNK (see 601158) (summary by Guo et al., 2019).
How et al. (1996) determined the sequences of the homologs of the human PDGFRB and CSF1R genes in the pufferfish (Fugu rubripes). Amino acid sequences of the Fugu and human PGFRB and CSF1R genes showed an overall homology of 45% and 39%, respectively.
In postnatal mouse brain, Erblich et al. (2011) found that Csf1r is expressed in microglia, but not in neurons, astrocytes, or glial cells.
Hampe et al. (1989) demonstrated that the FMS gene contains 21 small exons interrupted by introns ranging in size from 6.3 kb to less than 0.1 kb.
Roberts et al. (1988) demonstrated that a 5-prime untranslated exon of CSF1R is separated by a 26-kb intron from the 32-kb receptor coding sequences. Furthermore, the 3-prime end of the PDGFRB gene is located less than 0.5 kb upstream from this exon. The authors stated that the as yet unidentified CSF1R promoter/enhancer sequences may be confined to the nucleotides separating the 2 genes or could potentially lie within the PDGFR gene itself. Similarities in chromosomal localization, organization, and encoded amino acid sequences suggested that the CSF1R and PDGFR genes arose through duplication. The human homolog of the murine Fim2 proviral integration region corresponds to the 5-prime end of the FMS gene.
Pseudogene
During sequence analysis of the first intron of the human FMS gene, Sapi et al. (1994) identified an open reading frame encoding the ribosomal protein L7 (RPL7; 604166). The sequence was identical to the full-length RPL7 cDNA sequence but lacked any recognizable introns, had a 30-bp poly(A) tail, and was bracketed by 2 perfect direct repeats of 14 bp. Sapi et al. (1994) demonstrated that despite the fact that the 5-prime flanking region of the RPL7 sequence contained a potential TATA box upstream of an intact open reading frame, the pseudogene (RPL7P) was not actively transcribed.
The FMS oncogene was assigned to chromosome 5 by study of mouse-man somatic cell hybrids. The location was narrowed to 5q34 by the study of hamster-human cell hybrids with well-defined deletions of 5q (Groffen et al., 1984). The order on the long arm was found to be centromere--leuS--HEXB--EMTB--FMS--CHR. By in situ hybridization, Le Beau et al. (1986) assigned the FMS gene to chromosome 5q33.2 or 5q33.3 and the GMCSF (138960) gene to chromosome 5q23-q31.
Roberts et al. (1988) demonstrated that the CSF1R gene and the PDGFR1 (173410) gene are physically associated in a head-to-tail array, with less than 500 bp between the polyadenylation signal of the PDGFRB gene and the transcription start point of the CSF1R gene. By pulsed field gel electrophoresis, Eccles (1991) demonstrated that the same is true in the mouse where a 425-kb fragment hybridizes with the 3-prime end of PDGFR1 and the 5-prime end of CSF1R. In Fugu (pufferfish), How et al. (1996) demonstrated that the 2 genes are closely linked in a head-to-tail array with 2.2 kb of intergenic sequence.
Three mouse genomic domains, Fim1, Fim2, and Fim3, have been described as proviral integration regions frequently involved in the early stages of myeloblastic leukemogenesis induced in vivo or in vitro by the Friend murine leukemia virus. Fim2 has been identified as the 5-prime end of the Fms protooncogene. Van Cong et al. (1987, 1989) confirmed the localization of human FIM2/FMS on chromosome 5q33. By Southern blot analysis of DNA from human/rodent hybrids and by in situ hybridization, they mapped FIM1 to human chromosome 6p23-p22.3 and FIM3 to human chromosome 3q27.
Gross (2013) mapped the CSF1R gene to chromosome 5q32 based on an alignment of the CSF1R sequence (GenBank BC047521) with the genomic sequence (GRCh37).
Kondo et al. (2000) showed that a clonogenic common lymphoid progenitor, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B, and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin-2 receptor (146710) and GMCSF receptor (138981, 306250). Analysis of mutants of the beta-chain of the IL2 receptor revealed that the granulocyte and monocyte differentiation signals are triggered by different cytoplasmic domains, showing that the signaling pathways responsible for these unique developmental outcomes are separable. Finally, Kondo et al. (2000) showed that the endogenous myelomonocytic cytokine receptors for GM-CSF and macrophage colony-stimulating factor (CSF1R) are expressed at low to moderate levels on the more primitive hematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL2 (147680). Kondo et al. (2000) concluded that cytokine signaling can regulate cell fate decisions and proposed that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.
Faccio et al. (2003) retrovirally transduced beta-3 integrin (ITGB3; 173470) -/- osteoclast precursors with chimeric CSF1R constructs containing various cytoplasmic domain mutations and found that CSF1R tyr697 was required for normalization of osteoclastogenesis and ERK activation (see 176948). Overexpression of FOS (164810) normalized the number of ITGB3 -/- osteoclasts in vitro but not their ability to resorb dentin. Faccio et al. (2003) concluded that whereas CSF1R and alpha-V-beta-3 integrin collaborate in the osteoclastogenic process through shared activation of the ERK/FOS signaling pathway, the integrin is essential for matrix degradation.
Using fate mapping analysis, Ginhoux et al. (2010) showed that adult microglia derive from primitive macrophages. They showed that microglia develop in mice that lack colony-stimulating factor-1 (CSF1; 120420) but are absent in Csf1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors expressing Runx1 (151385) that arise before embryonic day 8. Ginhoux et al. (2010) concluded that their results identified microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
Le Beau et al. (1986) found that the FMS and GM-CSF genes were both deleted from chromosome 5q- in bone marrow cells of 2 patients with refractory anemia and del(5)(q15-q33.3) (see chromosome 5q deletion syndrome; 153550).
Morgan et al. (1986) pointed out that a break at 5q35 has been found in several cases of malignant histiocytosis, a neoplastic process characterized by fever, progressive wasting, lymphadenopathy, hepatosplenomegaly, and the proliferation of atypical histiocytes at all stages of maturation with frequent phagocytic activity. They suggested that at the molecular level the change in band 5q35 may affect the FMS oncogene responsible for the receptor for mononuclear-phagocyte growth factor and thereby have a role in causing malignant histiocytosis. Benz-Lemoine et al. (1988) also suggested that a breakpoint in 5q35 may be critical to the development of malignant histiocytosis.
Boultwood et al. (1991) found loss of both CSF1R alleles in 10 patients with myelodysplasia and a 5q deletion; 6 were hemizygous and 4 were homozygous for CSF1R loss. Boultwood et al. (1991) suggested that loss of this hemopoietic growth factor receptor gene may also be important in the pathogenesis of myeloid leukemia.
Somatic Mutations
Among 110 patients with myelodysplastic and leukemic disorders, Ridge et al. (1990) found somatic mutations in codon 969 of the CSF1R gene in 14 (12.7%) and in codon 301 in 2 (1.8%). The tyrosine residue at codon 969 was shown to be involved in a negative regulatory activity, which is disrupted by amino acid substitutions. Mutations at codon 301 lead to neoplastic transformation by ligand independence and constitutive tyrosine kinase activity of the receptor. Somatic mutations were most prevalent in chronic myelomonocytic leukemia (20%) and type M4 acute myeloblastic leukemia (23%), both of which are characterized by monocytic differentiation. One of 50 hematologically normal individuals had a 969C-T transition as a constitutional change, which may represent a predisposition to these particular malignancies.
Lamprecht et al. (2010) found that Reed-Sternberg cells in Hodgkin lymphoma (236000) demonstrated upregulation of CSF1R and CSF1 mRNA and constitutive activation of CSF1R, which correlated with increased proliferation of the Reed-Sternberg cells. Non-Hodgkin cell lines did not express either gene, suggesting that the expression in Reed-Sternberg cells was aberrant. Analysis of CSF1R transcripts in Reed-Sternberg cells showed use of an alternative transcription start site located about 6.2-kb upstream of the normal myeloid transcription start site: this sequence corresponded to a long terminal repeat (LTR) of the mammalian apparent LTR retrotransposon (MALR) THE1B family. LTRs derived from ancient retroviral infections have accumulated in the mammalian genome, and mammalian organisms have devised a number of surveillance mechanisms to silence these elements early in development, usually by DNA methylation. The LTR region was found to contain a number of putative binding sites for transcription factors (i.e., NFKB; 164011) that were expressed in the Reed-Sternberg cells. Further studies indicated that the LTR is normally repressed by epigenetic methylation, and that Reed-Sternberg cells had lost this methylation. In addition, nearly all Reed-Sternberg cells studied had lost expression of the transcriptional repressor CBFA2T3 (603870). LTR-driven CSF1R transcripts were also found in anaplastic large cell lymphoma. Lamprecht et al. (2010) suggested that inhibition of CSF1R signaling may be of therapeutic value in Hodgkin lymphoma.
Hereditary Diffuse Leukoencephalopathy With Spheroids
By linkage analysis followed by whole-exome sequencing of the family with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820) reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous mutation in the CSF1R gene (164770.0001). Sequencing of this gene in 13 additional probands with HDLS identified a different heterozygous mutation in each (see, e.g., 164770.0002-164770.0005). The mutations cosegregated with the disorder in all families for which DNA from multiple affected individuals was available, including the family reported by Baba et al. (2006). The phenotype was characterized by adult-onset of a rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often died of dementia within 6 years of onset. Brain imaging showed patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes. In vitro functional expression studies of some of the missense mutations indicated that the mutant proteins did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant proteins probably also act in a dominant-negative manner, since CSF1R assembles into homodimers. Overall, the findings indicated that a defect in microglial signaling and function resulting from CSF1R mutations can cause central nervous system degeneration.
In 7 Japanese probands with HDLS, Konno et al. (2014) identified 6 different heterozygous mutations in the CSF1R gene (see, e.g., 164770.0004; 164770.0006-164770.0008). Two of the mutations resulted in truncated proteins, indicating that haploinsufficiency is sufficient to cause the disorder. In vitro functional expression studies in HEK293 cells showed that none of the mutant CSF1R proteins, including those caused by missense mutations, were able to autophosphorylate. However, coexpression of the mutants with wildtype did not suppress wildtype autophosphorylation, indicating that the mutations do not act in a dominant-negative manner.
Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis
In 6 patients from 3 unrelated families with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476), Guo et al. (2019) identified homozygous or compound heterozygous mutations in the CSF1R gene (164770.0010-164770.0014). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Five different mutations were identified, including a nonsense and a missense variant in compound heterozygosity (see 164770.0010), an in-frame deletion and a deep intronic mutation in compound heterozygosity (see 164770.0012), and a deep intronic mutation in homozygosity (164770.0014). In vitro functional expression studies of 3 of the variants showed that they were associated with decreased JNK (MAPK8; 601158) phosphorylation, consistent with impaired function. The authors noted that the skeletal phenotype in these patients was not as severe as that observed in Csf1r-null mice, suggesting that some of the mutations likely result in hypomorphic alleles. However, the overall findings suggested that biallelic mutations that result in decreased CSF1R produce the skeletal phenotype, as heterozygous mutations that cause HDLS do not result in skeletal abnormalities. Moreover, Guo et al. (2019) noted that the heterozygous parental carriers in their study did not have manifestations, suggesting that HDLS mutations likely act via a dominant-negative effect.
In 2 unrelated patients with variable manifestations of BANDDOS, Oosterhof et al. (2019) identified homozygous mutations in the CSF1R gene (164770.0015 and 164770.0016). Functional studies of the variants and studies of patient cells were not performed, but 1 was a splice site mutation (164770.0015), predicted to result in a loss of function, and the other was a missense mutation (164770.0016), predicted to have a hypomorphic effect. The patient with the missense mutation did not have apparent skeletal involvement.
Dai et al. (2004) found that Csf1r-null mice had frequent spontaneous fractures and decreased bone strength associated with an expanded epiphyseal chondrocyte region, poorly formed cortex with disorganized collagen fibrils, and a severely disturbed matrix structure. Since Csf1r is expressed in osteoclasts, the findings suggesting that mutant mice had a deficiency of osteoclast-mediated regulation of osteoblasts during formation of lamellar bone.
Aikawa et al. (2010) found that mouse MOZ/TIF2 (see 601408)-induced AML stem cells with high expression of Csf1r had increased leukemia initiating activity than AML stem cells with same amount of MOZ/TIF2 protein and low expression of Csf1r, when transplanted in irradiated mice. The high Csf1r expressing cells had the phenotype of granulocyte-macrophage progenitors and differentiated monocytes. In mice with leukemia due to these cells, treatment with a drug-inducible suicide gene targeting Csf1r-expressing cells resulted in curing of the leukemia for up to 6 months compared to controls. Induction of AML was suppressed in Csf1r-deficient mice, and Csf1r inhibitors slowed the progression of MOZ/TIF2-induced AML. Increased Csf1r expression was due mainly to the hematopoietic transcription factor PU.1 (165170), which was required for the initiation and maintenance of MOZ/TIF2-induced AML by increasing transcription of Csf1r. Aikawa et al. (2010) suggested that CSF1R is crucial for leukemia induced by MOZ fusion and indicated that targeting of PU.1 may be a therapeutic option.
Erblich et al. (2011) found that Csf1r-null mice had postnatal developmental brain abnormalities, including enlarged ventricles, periventricular changes, parenchymal volume loss, thinning of the cerebral cortex, and propensity to hydrocephalus. These changes were associated with severely decreased numbers of microglia in the brain. Mutant mice also died early.
Oosterhof et al. (2019) found that knockdown of the csf1r homologs in zebrafish resulted in lack of microglia in the brain. Vertebral arches in mutant animals were smaller compared to controls, which the authors suggested may recapitulate osteopetrosis. These abnormalities were associated with downregulation of cux1 (116896), a transcription factor present in neurons.
In affected members of a large family with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820) originally reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous 2624T-C transition in exon 20 of the CSF1R gene, resulting in a met875-to-thr (M875T) substitution in a highly conserved residue in the intracellular tyrosine kinase domain. The mutation was not found in 1,436 controls. In vitro functional expression studies indicated that the mutant protein did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant protein probably also acts in a dominant-negative manner, since CSF1R assembles into homodimers.
In affected members of a large family with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), originally reported by Baba et al. (2006), Rademakers et al. (2012) identified a heterozygous 1897G-A transition in exon 14 of the CSF1R gene, resulting in a glu633-to-lys (E633K) substitution in a highly conserved residue in the intracellular tyrosine kinase domain. The mutation was not found in 1,436 controls. In vitro functional expression studies indicated that the mutant protein did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant protein probably also acts in a dominant-negative manner, since CSF1R assembles into homodimers.
In a pair of Norwegian monozygotic twins with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Rademakers et al. (2012) identified a heterozygous de novo A-to-G transition in intron 12 of the CSF1R gene (1754-2A-G), resulting in the skipping of exon 13, the in-frame loss of 34 consecutive amino acids, and the insertion of an alanine residue. The mutation was predicted to result in the loss of multiple amino acids in the intracellular tyrosine kinase domain.
In affected members of a family with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Rademakers et al. (2012) identified a heterozygous 2381T-C transition in exon 18 of the CSF1R gene, resulting in an ile794-to-thr (I794T) substitution in a highly conserved residue in the intracellular tyrosine kinase domain. The mutation was not found in 1,436 controls.
Konno et al. (2014) identified a heterozygous I794T substitution in 2 unrelated Japanese patients with HDLS. One had a family history of the disorder. In vitro functional expression assays in HEK293 cells showed that the mutant protein did not undergo autophosphorylation, but coexpression of the mutant with wildtype did not suppress wildtype autophosphorylation, indicating that the mutation does not act in a dominant-negative manner.
In a woman with sporadic occurrence of hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Rademakers et al. (2012) identified a heterozygous 2509G-T transversion in exon 19 of the CSF1R gene, resulting in an asp837-to-tyr (D837Y) substitution in a highly conserved residue in the intracellular tyrosine kinase domain. The mutation was not found in 1,436 controls. The patient was diagnosed clinically with a disorder resembling corticobasal syndrome, and was identified from a cohort of 93 patients with various neurologic symptoms. At age 43 years, she developed a gradual decline in expressing herself, word-finding, and performing motor tasks with her right hand and leg. About 2 years later, she had executive dysfunction, bradykinesia, hyperreflexia, apraxia, rigidity in the upper limbs, and spasticity in the lower limbs. There was rapid neurologic deterioration, and she died at age 50. Brain MRI showed localized white matter hyperintensities in the frontal and parietal white matter on T2-weighted images.
In a Japanese woman with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Konno et al. (2014) identified a heterozygous 1-bp insertion (c.2060insT) in the CSF1R gene, resulting in a frameshift and premature termination (Ser688GlufsTer13). The mutation was not found in the dbSNP database or in 124 healthy controls. She had onset of the disorder at age 41 years and died at age 54; there was no family history of a similar disorder. The mutant protein was barely detectable in brain tissue from the patient, suggesting that it undergoes nonsense-mediated mRNA decay, resulting in haploinsufficiency. In vitro functional expression assays in HEK293 cells showed that the mutant protein did not undergo autophosphorylation, but coexpression of the mutant with wildtype did not suppress wildtype autophosphorylation, indicating that the mutation does not act in a dominant-negative manner.
In a Japanese man with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Konno et al. (2014) identified a heterozygous G-to-T transversion in intron 18 of the CSF1R gene (c.2442+1G-T), resulting in a splice site mutation. Patient tissue showed 3 aberrant splice variants with skipped exon 18, all resulting in truncated proteins. Western blot analysis of patient brain tissue showed markedly decreased expression of the full-length protein. In vitro functional expression assays in HEK293 cells showed that the mutant protein did not undergo autophosphorylation, but coexpression of the mutant with wildtype did not suppress wildtype autophosphorylation, indicating that the mutation does not act in a dominant-negative manner.
In a Japanese woman with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), Konno et al. (2014) identified a heterozygous c.2342C-A transversion in the CSF1R gene, resulting in an ala781-to-glu (A781E) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation was not found in the dbSNP database or in 124 controls. In vitro functional expression assays in HEK293 cells showed that the mutant protein did not undergo autophosphorylation, but coexpression of the mutant with wildtype did not suppress wildtype autophosphorylation, indicating that the mutation does not act in a dominant-negative manner.
In affected members of a family (FTD368) with hereditary diffuse leukoencephalopathy with spheroids (HDLS; 221820), originally reported by Knopman et al. (1996), Nicholson et al. (2013) identified a heterozygous c.2345G-A transition in exon 18 of the CSF1R gene, resulting in an arg782-to-his (R782H) substitution in the kinase domain. The mutation segregated with the disorder in the family and was not found in 1,089 white, non-Hispanic control individuals. In vitro functional expression studies in HeLa cells showed that the R782H mutation abrogated CSF1R autophosphorylation, which would inhibit downstream signaling. Since the family had originally received a clinicopathologic diagnosis of pigmented orthochromatic leukodystrophy (POLD), the findings indicated that POLD and HDLS are a single disease entity.
In a 4-year-old Brazilian boy (family A), with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476), Guo et al. (2019) identified compound heterozygous mutations in the CSF1R gene: a c.395C-T transition (c.395C-T, NM_005211), resulting in a pro132-to-leu (P132L) substitution, and a c.1441C-T transition, resulting in a gln481-to-ter (Q481X; 164770.0011) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P132L variant was found once in the heterozygous state in the gnomAD database, and c.1441C-T was found in 1 control from 1,200 elderly healthy Brazilians. Analysis of patient cells indicated that the nonsense mutation resulted in nonsense-mediated mRNA decay. In vitro functional expression studies showed that cells carrying the P132L mutation had significantly decreased CSF1R-mediated phosphorylation of JNK (601158), consistent with a loss of function.
For discussion of the c.1441C-T transition (c.1441C-T, NM_005211) in the CSF1R gene, resulting in a gln481-to-ter (Q481X) substitution, that was found in compound heterozygous state in a patient with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476) by Guo et al. (2019), see 164770.0010.
In a 37-year-old Japanese woman (family B) with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476), Guo et al. (2019) identified compound heterozygous mutations in the CSF1R gene: a G-to-A transition (c.1859-119G-A, NM_005211) in intron 13, resulting in aberrant splicing, and a 3-bp in-frame deletion (c.1879_1881del; 164770.0013), resulting in the deletion of lys627 in the intracellular kinase domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found in any available database, including gnomAD. Analysis of patient cells showed that the c.1859-119G-A variant resulted in a 117-bp insertion, leading to an elongated protein (Ser620delins40). In vitro functional expression studies showed that cells carrying both of these mutations significantly decreased CSF1R-mediated phosphorylation of JNK (601158), consistent with a loss of function.
For discussion of the 3-bp in-frame deletion (c.1879_1881del, NM_005211) in the CSF1R gene, resulting in the deletion of lys627 in the intracellular kinase domain, that was found in compound heterozygous state in a patient with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476) by Guo et al. (2019), see 164770.0012.
In 2 sibs, born of consanguineous Chaldean parents (family C), with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476), Guo et al. (2019) identified a homozygous 2-bp deletion deep within intron 14 of the CSF1R gene (c.1969+115_1969+116, NM_005211). The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR analysis of patients cells showed an abnormal transcript with a 99-bp insertion, resulting in premature termination (Pro658SerfsTer24). However, the mutation was subject to nonsense-mediated mRNA decay, suggesting a complete loss of function.
In a male infant, born of consanguineous parents of Native Alaskan ancestry (family CSF1R_01), with brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS; 618476), Oosterhof et al. (2019) identified a homozygous G-to-C transversion (c.1754-1G-C, NM_005211.3) in intron 12 of the CSF1R gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family. The variant was predicted to result in the skipping of exon 13 and produce an in-frame protein product change (Gly585_Lys619delinsAla) within the tyrosine kinase domain. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patient died of bacteremia at 10 months of age.
In a 24-year-old man, born of consanguineous Arab parents (family CSF1R_02) with brain abnormalities and neurodegeneration (BANDDOS; 618476), Oosterhof et al. (2019) identified a homozygous c.1929C-A transversion in intron 14 of the CSF1R gene, resulting in a his643-to-gln (H643Q) substitution in the kinase domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function, most likely with a hypomorphic effect. X-rays showed no evidence of osteopetrosis and there was no known history of hypocalcemia. A similarly affected brother had died at age 21 years, but DNA was not available for study.
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