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* 600820

ARCHAIN 1; ARCN1


Alternative titles; symbols

COATOMER PROTEIN COMPLEX, SUBUNIT DELTA; COPD
COP, DELTA


HGNC Approved Gene Symbol:ARCN1

Cytogenetic location:11q23.3   Genomic coordinates(GRCh38) :11:118,572,409-118,603,033 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q23.3 Short stature-micrognathia syndrome 617164AD3

TEXT

Description

ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking (Xu et al., 2010).


Cloning and Expression

Radice et al. (1995) identified a gene approximately 50-kb telomeric to MLL (159555) on chromosome 11, a locus disrupted in certain leukemia-associated translocation chromosomes. A 200-kb genomic fragment from a YAC that included MLL was used to screen a cDNA library of the R54;11 cell line, which carries a translocation chromosome t(4;11)(q21; q23). The cDNA sequence predicts a 511-amino acid protein that shares similarity with predicted proteins from rice (Oryza sativa) and Drosophila. Because of this ancient conservation, the authors proposed the name archain (ARCN1).Radice et al. (1995) detected 4-kb ARCN1 transcripts by Northern blot analysis in all tissues examined.

The protein encoded by the ARCN1 gene, the coatomer protein delta-COP, probably plays a fundamental role in eukaryotic cell biology.Tunnacliffe et al. (1996) demonstrated that it is conserved across diverse eukaryotes. Very close or identical matches were seen in rat and cow; highly significant matches were seen with 2 plant species, A. thaliana (cress) and S. tuberosum (potato). Of particular biologic significance was the match with a sequence on yeast chromosome VI, from whichTunnacliffe et al. (1996) were able to determine the yeast archain gene and protein sequence. Unpublished data indicated that in situ hybridization on mouse embryo sections showed archain transcripts throughout the whole animal.

By fluorescence immunohistochemical analysis,Xu et al. (2010) localized Arcn1 to Golgi, endoplasmic reticulum (ER), and cytoplasmic vesicles of mouse melanocytes. Arcn1 partly colocalized with beta-COP (COPB1;600959) in mouse melanocytes and Neuro2a cells.


Mapping

Radice et al. (1995) mapped the ARCN1 gene to chromosome 11q23.3, approximately 50 kb telomeric to MLL.

Xu et al. (2010) stated that the mouse Arcn1 gene maps to chromosome 9.


Gene Function

Izumi et al. (2016) studied a skin fibroblast cell line in which ARCN1 had been knocked down by siRNA and observed upregulation of endoplasmic reticulum (ER) stress markers compared to control fibroblasts. Artificial induction of ER stress by the addition of thapsigargin and tunicamycin triggered ARCN1 overexpression, although the amount of ARCN1 remained unchanged, suggesting increased ARCN1 turnover during the ER stress response.Izumi et al. (2016) suggested that ARCN1 plays a major role in ameliorating induction of the stress response. In addition, the authors observed accumulation of type I collagen in ARCN1 knockdown cell lysates, and immunoblotting demonstrated the reduction of secreted type I collagen in culture media, suggesting that ARCN1 reduction causes intracellular accumulation of type I collagen as a result of defective intracellular protein transport. Addition of an ER-Golgi transport inhibitor resulted in a similar accumulation of intracellular type I collagen, whereas the addition of thapsigargin and tunicamycin did not.Izumi et al. (2016) concluded that ARCN1 is directly responsible for the intracellular transport of type I collagen and that the collagen transport defect is not secondary to the ER stress response.


Molecular Genetics

By whole-exome sequencing in 4 patients with short stature-micrognathia syndrome (SSMG;617164) manifest as rhizomelic short stature with microcephaly, micrognathia, and developmental delay,Izumi et al. (2016) identified heterozygous truncating mutations in the ARCN1 gene (600820.0001-600820.0003). One of the probands (see600820.0003) was also heterozygous for a missense mutation in the SYT1 gene (D233N; see185605), whichIzumi et al. (2016) suggested might have contributed to the additional feature of seizures in that patient; however, given that all 4 patients with ARCN1 mutations exhibited comparable degrees of developmental delay and intellectual disability, the authors concluded that the ARCN1 mutations likely play a major role in the neurologic features observed in this syndrome, and that ARCN1 is probably required for normal brain growth and cognitive development.

In a 2-year-old boy with rhizomelic short stature, microcephaly, and retrognathia as well as a febrile illness-associated glycosylation defect, who was negative for mutation in the PGM1 (171900) gene and had normal PGM1 enzyme activity,Reunert et al. (2019) performed whole-exome analysis and identified a de novo heterozygous 1-bp duplication in the ARCN1 gene (600820.0004).

In a 4.75-year-old boy with SSMG and epilepsy,Tidwell et al. (2020) identified heterozygosity for a de novo splicing mutation in the ARCN1 gene (600820.0005). Functional analysis showed that the splice variant resulted in a frameshift and premature termination codon.

Through international collaboration using GeneMatcher and physician referrals,Ritter et al. (2022) identified 9 patients and 5 fetal cases with short stature-micrognathia syndrome and heterozygous truncating ARCN1 mutations (see, e.g.,600820.0005-600820.0007). The authors noted that variant type or location did not seem to correlate with the severity of the phenotype either in fetuses or in living patients, and the observation of striking intrafamilial variability suggested that genetic modifiers or environmental effects might determine phenotypic severity of the disorder.


Animal Model

By screening for diluted coat color and ataxia in N-ethyl-N-nitrosourea-induced mouse mutants,Xu et al. (2010) identified the autosomal recessive mutation neurologic-17 (nur17). Nur17 mice were smaller than controls and exhibited mild but progressive coat color dilution and ataxic movements at 2 months of age. Nur17 cerebellum showed normal morphology at 1 month of age, but at 2 months it exhibited Purkinje cell (PC) degeneration in part of lobule VI and in lobules VII to X. Positional cloning and sequencing revealed a T-C transition in exon 10 of the Arcn1 gene in nur17 mice, resulting in an ile422-to-thr (I422T) substitution near the cargo-binding site, which recognizes arg-based ER localization signals. The nur17 mutation did not cause RNA instability, improper processing, or mislocalization of Arcn1 in nur17 melanocytes, but transgenic expression of wildtype Arcn1 rescued the phenotype in nur17 mice. Electron microscopy of nur17 cerebellum revealed abnormal accumulation of proteins in PC dendrites and perinuclear region, accumulation of the ER stress marker Chop (DDIT3;126337) in PC bodies, and neurofibrillary tangles in PC bodies and dendrites that did not appear to contain hyperphosphorylated tau (MAPT;157140). Nur17 melanocytes showed impaired maturation and glycosylation of Tyrp1 (115501), which is involved in melanosome biogenesis, suggesting altered ER-Golgi and/or intra-Golgi trafficking.


ALLELIC VARIANTS (7 Selected Examples):

.0001 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 2-BP DEL, NT157
  
RCV000257962

In a father and daughter (patients 3 and 4) who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG;617164),Izumi et al. (2016) identified heterozygosity for a 2-bp deletion (c.157_158del, NM_001655) in the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Ser53CysfsTer39). The mutation arose de novo in the father, who was originally described byVerloes et al. (1997). Skin fibroblast samples from both patients showed significantly reduced expression of ARCN1 compared to control, and Western blot analysis of the father's fibroblasts showed mildly reduced ARCN1 protein. In addition, an ER stress marker, BiP (HSPA5;138120), was elevated in the father's fibroblast sample compared to control.


.0002 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, SER87TER
  
RCV000257989

In a 3.3-year-old Japanese girl (patient 1) who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG;617164),Izumi et al. (2016) identified heterozygosity for a de novo c.260C-A transversion (c.260C-A, NM_001655) in exon 2 of the ARCN1 gene, resulting in a ser87-to-ter (S87X) substitution.


.0003 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DEL, NT633
  
RCV000257942

In a 7-year-old boy (patient 2) from Singapore who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG;617164),Izumi et al. (2016) identified heterozygosity for a de novo 1-bp deletion (c.633del, NM_001655) in exon 4 of the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Val212TrpfsTer15). The proband was also heterozygous for a de novo missense mutation in the SYT1 gene (D233N; see185605), whichIzumi et al. (2016) suggested might have contributed to the additional feature of seizures in this patient.


.0004 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DUP, 380T
  
RCV002281588

In a 2-year-old boy with rhizomelic short stature, microcephaly, and retrognathia, as well as a febrile illness-associated glycosylation defect (SSMG;617164),Reunert et al. (2019) identified heterozygosity for a de novo 1-bp duplication (ENST00000264028.4, c.380dupT) in the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Leu127PhefsTer14). Functional studies of the variant were not performed.


.0005 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, IVS4, A-G, -15
  
RCV000993710...

In a 4.75-year-old boy with rhizomelic short stature, microcephaly, microretrognathia, significant global developmental delay, and epilepsy (SSMG;617164),Tidwell et al. (2020) identified heterozygosity for a de novo splicing mutation (c.654-15A-G, NM_001655.5) in intron 4 of the ARCN1 gene. Sanger sequencing confirmed the variant and its absence in his parents. Analysis of cDNA generated from patient blood showed a novel sequence between exons 4 and 5, with retention of 14 nucleotides from intron 4, causing a frameshift predicted to result in a premature termination codon (Pro219PhefsTer13).

In a 3-year-old girl (C2) with short stature, microcephaly, micrognathia, cleft palate, and liver function abnormalities, but who had normal psychomotor development,Ritter et al. (2022) identified heterozygosity for the c.654-15A-G splicing mutation in the ARCN1 gene.


.0006 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, ARG312TER
  
RCV001335853

In 3 unrelated patients with short stature, micrognathia, and developmental delay (SSMG;617164),Ritter et al. (2022) identified heterozygosity for a c.934C-T transition (c.934C-T, NM_001655.4) in exon 6 of the ARCN1 gene, resulting in an arg312-to-ter (R312X) substitution. Two of the patients were male, a 4-year-old (C1) and a 9-month-old (C3), and both also exhibited microcephaly and genitourinary anomalies: both had hypospadias, and the older boy also had bifid scrotum and cryptorchidism, whereas the younger had ambiguous genitalia. The boys also had carbohydrate-deficient transferrin and liver function abnormalities, and the younger was also reported to have giant cell hepatitis. The other patient was a 2-year-old Norwegian girl (N1) who also showed liver function abnormalities, and who developed hepatoblastoma by age 15 months and underwent resection and chemotherapy.


.0007 SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DUP, NT1001
  
RCV002281589

In a 36-year-old woman (F1) with rhizomelic short stature, micrognathia, and bifid uvula (SSMG;617164),Ritter et al. (2022) identified heterozygosity for a 1-bp duplication (c.1001dup, NM_001655.4) in exon 7 of the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Asp334GlufsTer2). The mildly affected proband had given birth to 4 affected fetuses resulting in fetal demise, suggesting the possible contribution of genetic modifiers or environmental effects in determining phenotypic severity. The ARCN1 duplication was present in the 3 fetuses that could be tested.


REFERENCES

  1. Izumi, K., Brett, M., Nishi, E., Drunat, S., Tan, E.-S., Fujiki, K., Lebon, S., Cham, B., Masuda, K., Arakawa, M., Jacqunet, A., Yamazumi, Y., and 12 others.ARCN1 mutations cause a recognizable craniofacial syndrome due to COPI-mediated transport defects. Am. J. Hum. Genet. 99: 451-459, 2016. [PubMed:27476655,images,related citations] [Full Text]

  2. Radice, P., Pensotti, V., Jones, C., Perry, H., Pierotti, M. A., Tunnacliffe, A.The human archain gene, ARCN1, has highly conserved homologs in rice and Drosophila. Genomics 26: 101-106, 1995. [PubMed:7782067,related citations] [Full Text]

  3. Reunert, J., Rust, S., Gruneberg, M., Seelhofer, A., Kurz, D., Ocker, V., Weber, D., Fingerhut, R., Marquardt, T.Transient N-glycosylation abnormalities likely due to a de novo loss-of-function mutation in the delta subunit of coat protein I. Am. J. Med. Genet. 179A: 1371-1375, 2019. [PubMed:31075182,related citations] [Full Text]

  4. Ritter, A. L., Gold, J., Hayashi, H., Ackermann, A. M., Hanke, S., Skraban, C., Cuddapah, S., Bhoj, E., Li, D., Kuroda, Y., Wen, J., Takeda, R., and 30 others.Expanding the phenotypic spectrum of ARCN1-related syndrome. Genet. Med. 24: 1227-1237, 2022. [PubMed:35300924,related citations] [Full Text]

  5. Tidwell, T., Deshotel, M., Palumbos, J., Miller, C., Bayrak-Toydemir, P., Carey, J. C.Novel de novo ARCN1 intronic variant causes rhizomelic short stature with microretrognathia and developmental delay. Cold Spring Harbor Molec. Case Stud. 6: a005728, 2020. [PubMed:33154040,images,related citations] [Full Text]

  6. Tunnacliffe, A., van de Vrugt, H., Pensotti, V., Radice, P.The coatomer protein delta-COP, encoded by the archain gene, is conserved across diverse eukaryotes. Mammalian Genome 7: 784-786, 1996. [PubMed:8854871,related citations] [Full Text]

  7. Verloes, A., Lesenfants, S., Misson, J.-P., Galand, A., Koulischer, L.Microcephaly, muscular build, rhizomelia, and cataracts: description of a possible recessive syndrome and some comments on the use of electronic databases in syndromology. Am. J. Med. Genet. 68: 455-460, 1997. [PubMed:9021021,related citations] [Full Text]

  8. Xu, X., Kedlaya, R., Higuchi, H., Ikeda, S., Justice, M. J., Setaluri, V., Ikeda, A.Mutation in archain 1, a subunit of COPI coatomer complex, causes diluted coat color and Purkinje cell degeneration. PLoS Genet. 6: e1000956, 2010. Note: Electronic Article. [PubMed:20502676,images,related citations] [Full Text]


Marla J. F. O'Neill - updated : 09/06/2022
Marla J. F. O'Neill - updated : 10/19/2016
Patricia A. Hartz - updated : 09/14/2016
Creation Date:
Alan F. Scott : 10/2/1995
alopez : 09/06/2022
alopez : 07/01/2019
carol : 10/19/2016
mgross : 09/14/2016
jenny : 12/12/1996
mark : 4/7/1996
joanna : 2/2/1996
mark : 10/2/1995

* 600820

ARCHAIN 1; ARCN1


Alternative titles; symbols

COATOMER PROTEIN COMPLEX, SUBUNIT DELTA; COPD
COP, DELTA


HGNC Approved Gene Symbol: ARCN1

Cytogenetic location: 11q23.3   Genomic coordinates(GRCh38) : 11:118,572,409-118,603,033(from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q23.3 Short stature-micrognathia syndrome 617164 Autosomal dominant 3

TEXT

Description

ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking (Xu et al., 2010).


Cloning and Expression

Radice et al. (1995) identified a gene approximately 50-kb telomeric to MLL (159555) on chromosome 11, a locus disrupted in certain leukemia-associated translocation chromosomes. A 200-kb genomic fragment from a YAC that included MLL was used to screen a cDNA library of the R54;11 cell line, which carries a translocation chromosome t(4;11)(q21; q23). The cDNA sequence predicts a 511-amino acid protein that shares similarity with predicted proteins from rice (Oryza sativa) and Drosophila. Because of this ancient conservation, the authors proposed the name archain (ARCN1). Radice et al. (1995) detected 4-kb ARCN1 transcripts by Northern blot analysis in all tissues examined.

The protein encoded by the ARCN1 gene, the coatomer protein delta-COP, probably plays a fundamental role in eukaryotic cell biology. Tunnacliffe et al. (1996) demonstrated that it is conserved across diverse eukaryotes. Very close or identical matches were seen in rat and cow; highly significant matches were seen with 2 plant species, A. thaliana (cress) and S. tuberosum (potato). Of particular biologic significance was the match with a sequence on yeast chromosome VI, from which Tunnacliffe et al. (1996) were able to determine the yeast archain gene and protein sequence. Unpublished data indicated that in situ hybridization on mouse embryo sections showed archain transcripts throughout the whole animal.

By fluorescence immunohistochemical analysis, Xu et al. (2010) localized Arcn1 to Golgi, endoplasmic reticulum (ER), and cytoplasmic vesicles of mouse melanocytes. Arcn1 partly colocalized with beta-COP (COPB1; 600959) in mouse melanocytes and Neuro2a cells.


Mapping

Radice et al. (1995) mapped the ARCN1 gene to chromosome 11q23.3, approximately 50 kb telomeric to MLL.

Xu et al. (2010) stated that the mouse Arcn1 gene maps to chromosome 9.


Gene Function

Izumi et al. (2016) studied a skin fibroblast cell line in which ARCN1 had been knocked down by siRNA and observed upregulation of endoplasmic reticulum (ER) stress markers compared to control fibroblasts. Artificial induction of ER stress by the addition of thapsigargin and tunicamycin triggered ARCN1 overexpression, although the amount of ARCN1 remained unchanged, suggesting increased ARCN1 turnover during the ER stress response. Izumi et al. (2016) suggested that ARCN1 plays a major role in ameliorating induction of the stress response. In addition, the authors observed accumulation of type I collagen in ARCN1 knockdown cell lysates, and immunoblotting demonstrated the reduction of secreted type I collagen in culture media, suggesting that ARCN1 reduction causes intracellular accumulation of type I collagen as a result of defective intracellular protein transport. Addition of an ER-Golgi transport inhibitor resulted in a similar accumulation of intracellular type I collagen, whereas the addition of thapsigargin and tunicamycin did not. Izumi et al. (2016) concluded that ARCN1 is directly responsible for the intracellular transport of type I collagen and that the collagen transport defect is not secondary to the ER stress response.


Molecular Genetics

By whole-exome sequencing in 4 patients with short stature-micrognathia syndrome (SSMG; 617164) manifest as rhizomelic short stature with microcephaly, micrognathia, and developmental delay, Izumi et al. (2016) identified heterozygous truncating mutations in the ARCN1 gene (600820.0001-600820.0003). One of the probands (see 600820.0003) was also heterozygous for a missense mutation in the SYT1 gene (D233N; see 185605), which Izumi et al. (2016) suggested might have contributed to the additional feature of seizures in that patient; however, given that all 4 patients with ARCN1 mutations exhibited comparable degrees of developmental delay and intellectual disability, the authors concluded that the ARCN1 mutations likely play a major role in the neurologic features observed in this syndrome, and that ARCN1 is probably required for normal brain growth and cognitive development.

In a 2-year-old boy with rhizomelic short stature, microcephaly, and retrognathia as well as a febrile illness-associated glycosylation defect, who was negative for mutation in the PGM1 (171900) gene and had normal PGM1 enzyme activity, Reunert et al. (2019) performed whole-exome analysis and identified a de novo heterozygous 1-bp duplication in the ARCN1 gene (600820.0004).

In a 4.75-year-old boy with SSMG and epilepsy, Tidwell et al. (2020) identified heterozygosity for a de novo splicing mutation in the ARCN1 gene (600820.0005). Functional analysis showed that the splice variant resulted in a frameshift and premature termination codon.

Through international collaboration using GeneMatcher and physician referrals, Ritter et al. (2022) identified 9 patients and 5 fetal cases with short stature-micrognathia syndrome and heterozygous truncating ARCN1 mutations (see, e.g., 600820.0005-600820.0007). The authors noted that variant type or location did not seem to correlate with the severity of the phenotype either in fetuses or in living patients, and the observation of striking intrafamilial variability suggested that genetic modifiers or environmental effects might determine phenotypic severity of the disorder.


Animal Model

By screening for diluted coat color and ataxia in N-ethyl-N-nitrosourea-induced mouse mutants, Xu et al. (2010) identified the autosomal recessive mutation neurologic-17 (nur17). Nur17 mice were smaller than controls and exhibited mild but progressive coat color dilution and ataxic movements at 2 months of age. Nur17 cerebellum showed normal morphology at 1 month of age, but at 2 months it exhibited Purkinje cell (PC) degeneration in part of lobule VI and in lobules VII to X. Positional cloning and sequencing revealed a T-C transition in exon 10 of the Arcn1 gene in nur17 mice, resulting in an ile422-to-thr (I422T) substitution near the cargo-binding site, which recognizes arg-based ER localization signals. The nur17 mutation did not cause RNA instability, improper processing, or mislocalization of Arcn1 in nur17 melanocytes, but transgenic expression of wildtype Arcn1 rescued the phenotype in nur17 mice. Electron microscopy of nur17 cerebellum revealed abnormal accumulation of proteins in PC dendrites and perinuclear region, accumulation of the ER stress marker Chop (DDIT3; 126337) in PC bodies, and neurofibrillary tangles in PC bodies and dendrites that did not appear to contain hyperphosphorylated tau (MAPT; 157140). Nur17 melanocytes showed impaired maturation and glycosylation of Tyrp1 (115501), which is involved in melanosome biogenesis, suggesting altered ER-Golgi and/or intra-Golgi trafficking.


ALLELIC VARIANTS7 Selected Examples):

.0001   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 2-BP DEL, NT157
SNP: rs886040858, ClinVar: RCV000257962

In a father and daughter (patients 3 and 4) who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG; 617164), Izumi et al. (2016) identified heterozygosity for a 2-bp deletion (c.157_158del, NM_001655) in the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Ser53CysfsTer39). The mutation arose de novo in the father, who was originally described by Verloes et al. (1997). Skin fibroblast samples from both patients showed significantly reduced expression of ARCN1 compared to control, and Western blot analysis of the father's fibroblasts showed mildly reduced ARCN1 protein. In addition, an ER stress marker, BiP (HSPA5; 138120), was elevated in the father's fibroblast sample compared to control.


.0002   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, SER87TER
SNP: rs886040859, ClinVar: RCV000257989

In a 3.3-year-old Japanese girl (patient 1) who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG; 617164), Izumi et al. (2016) identified heterozygosity for a de novo c.260C-A transversion (c.260C-A, NM_001655) in exon 2 of the ARCN1 gene, resulting in a ser87-to-ter (S87X) substitution.


.0003   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DEL, NT633
SNP: rs886040860, ClinVar: RCV000257942

In a 7-year-old boy (patient 2) from Singapore who had rhizomelic short stature with microcephaly, micrognathia, and developmental delay (SSMG; 617164), Izumi et al. (2016) identified heterozygosity for a de novo 1-bp deletion (c.633del, NM_001655) in exon 4 of the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Val212TrpfsTer15). The proband was also heterozygous for a de novo missense mutation in the SYT1 gene (D233N; see 185605), which Izumi et al. (2016) suggested might have contributed to the additional feature of seizures in this patient.


.0004   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DUP, 380T
SNP: rs2497682237, ClinVar: RCV002281588

In a 2-year-old boy with rhizomelic short stature, microcephaly, and retrognathia, as well as a febrile illness-associated glycosylation defect (SSMG; 617164), Reunert et al. (2019) identified heterozygosity for a de novo 1-bp duplication (ENST00000264028.4, c.380dupT) in the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Leu127PhefsTer14). Functional studies of the variant were not performed.


.0005   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, IVS4, A-G, -15
SNP: rs1591385240, ClinVar: RCV000993710, RCV004783874

In a 4.75-year-old boy with rhizomelic short stature, microcephaly, microretrognathia, significant global developmental delay, and epilepsy (SSMG; 617164), Tidwell et al. (2020) identified heterozygosity for a de novo splicing mutation (c.654-15A-G, NM_001655.5) in intron 4 of the ARCN1 gene. Sanger sequencing confirmed the variant and its absence in his parents. Analysis of cDNA generated from patient blood showed a novel sequence between exons 4 and 5, with retention of 14 nucleotides from intron 4, causing a frameshift predicted to result in a premature termination codon (Pro219PhefsTer13).

In a 3-year-old girl (C2) with short stature, microcephaly, micrognathia, cleft palate, and liver function abnormalities, but who had normal psychomotor development, Ritter et al. (2022) identified heterozygosity for the c.654-15A-G splicing mutation in the ARCN1 gene.


.0006   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, ARG312TER
SNP: rs1565363889, ClinVar: RCV001335853

In 3 unrelated patients with short stature, micrognathia, and developmental delay (SSMG; 617164), Ritter et al. (2022) identified heterozygosity for a c.934C-T transition (c.934C-T, NM_001655.4) in exon 6 of the ARCN1 gene, resulting in an arg312-to-ter (R312X) substitution. Two of the patients were male, a 4-year-old (C1) and a 9-month-old (C3), and both also exhibited microcephaly and genitourinary anomalies: both had hypospadias, and the older boy also had bifid scrotum and cryptorchidism, whereas the younger had ambiguous genitalia. The boys also had carbohydrate-deficient transferrin and liver function abnormalities, and the younger was also reported to have giant cell hepatitis. The other patient was a 2-year-old Norwegian girl (N1) who also showed liver function abnormalities, and who developed hepatoblastoma by age 15 months and underwent resection and chemotherapy.


.0007   SHORT STATURE-MICROGNATHIA SYNDROME

ARCN1, 1-BP DUP, NT1001
SNP: rs2497713595, ClinVar: RCV002281589

In a 36-year-old woman (F1) with rhizomelic short stature, micrognathia, and bifid uvula (SSMG; 617164), Ritter et al. (2022) identified heterozygosity for a 1-bp duplication (c.1001dup, NM_001655.4) in exon 7 of the ARCN1 gene, causing a frameshift predicted to result in a premature termination codon (Asp334GlufsTer2). The mildly affected proband had given birth to 4 affected fetuses resulting in fetal demise, suggesting the possible contribution of genetic modifiers or environmental effects in determining phenotypic severity. The ARCN1 duplication was present in the 3 fetuses that could be tested.


REFERENCES

  1. Izumi, K., Brett, M., Nishi, E., Drunat, S., Tan, E.-S., Fujiki, K., Lebon, S., Cham, B., Masuda, K., Arakawa, M., Jacqunet, A., Yamazumi, Y., and 12 others.ARCN1 mutations cause a recognizable craniofacial syndrome due to COPI-mediated transport defects. Am. J. Hum. Genet. 99: 451-459, 2016. [PubMed: 27476655] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.011]

  2. Radice, P., Pensotti, V., Jones, C., Perry, H., Pierotti, M. A., Tunnacliffe, A.The human archain gene, ARCN1, has highly conserved homologs in rice and Drosophila. Genomics 26: 101-106, 1995. [PubMed: 7782067] [Full Text: https://doi.org/10.1016/0888-7543(95)80087-3]

  3. Reunert, J., Rust, S., Gruneberg, M., Seelhofer, A., Kurz, D., Ocker, V., Weber, D., Fingerhut, R., Marquardt, T.Transient N-glycosylation abnormalities likely due to a de novo loss-of-function mutation in the delta subunit of coat protein I. Am. J. Med. Genet. 179A: 1371-1375, 2019. [PubMed: 31075182] [Full Text: https://doi.org/10.1002/ajmg.a.61190]

  4. Ritter, A. L., Gold, J., Hayashi, H., Ackermann, A. M., Hanke, S., Skraban, C., Cuddapah, S., Bhoj, E., Li, D., Kuroda, Y., Wen, J., Takeda, R., and 30 others.Expanding the phenotypic spectrum of ARCN1-related syndrome. Genet. Med. 24: 1227-1237, 2022. [PubMed: 35300924] [Full Text: https://doi.org/10.1016/j.gim.2022.02.005]

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Contributors:
Marla J. F. O'Neill - updated : 09/06/2022
Marla J. F. O'Neill - updated : 10/19/2016
Patricia A. Hartz - updated : 09/14/2016

Creation Date:
Alan F. Scott : 10/2/1995

Edit History:
alopez : 09/06/2022
alopez : 07/01/2019
carol : 10/19/2016
mgross : 09/14/2016
jenny : 12/12/1996
mark : 4/7/1996
joanna : 2/2/1996
mark : 10/2/1995



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2026 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2026 Johns Hopkins University.
Printed: Feb. 8, 2026

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