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* 607783

MESODERM DEVELOPMENT LRP CHAPERONE; MESD


Alternative titles; symbols

MESODERM DEVELOPMENT CANDIDATE GENE 2; MESDC2
MESODERM DEVELOPMENT GENE
KIAA0081
BOCA, DROSOPHILA, HOMOLOG OF; BOCA


Other entities represented in this entry:

MESDC2/SENP1 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol:MESD

Cytogenetic location:15q25.1   Genomic coordinates(GRCh38) :15:80,946,289-80,989,819 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q25.1 Osteogenesis imperfecta, type XX 618644AR3

TEXT

Cloning and Expression

By sequencing cDNAs randomly selected from a cDNA library derived from the human immature myeloid cell line KG-1,Nagase et al. (1995) isolated a cDNA encoding MESDC2, which they designated KIAA0081. The predicted 233-amino acid protein contains at least 1 putative transmembrane region. Northern blot analysis detected expression in all tissues tested except peripheral blood leukocytes.

Wines et al. (2001) cloned mouse Mesdc2, which encodes a 223-amino acid protein that shares 82% identity with the 234-amino acid human protein. MESDC2 was predicted to have an N-terminal transmembrane domain. Northern blot analysis detected a 1.8-kb transcript in mouse embryos throughout development and in all adult mouse tissues tested, except skeletal muscle.


Mapping

Nagase et al. (1995) mapped the MESDC2 gene to chromosome 15 by analysis of human-rodent hybrid cell lines.

By radiation hybrid analysis and sequencing a BAC contig,Wines et al. (2001) mapped the MESCD2 gene to chromosome 15q23-q25. They mapped the mouse Mesdc2 gene to a region of chromosome 7 that shares homology of synteny with human chromosome 15q23-q25.

Veltman et al. (2005) stated that the MESDC2 gene maps to chromosome 15q25.

Gross (2019) mapped the MESD gene to chromosome 15q25.1 based on an alignment of the MESD sequence (GenBankBC009210) with the genomic sequence (GRCh38).


Gene Function

Hsieh et al. (2003) demonstrated that Mesdc2, a gene identified in the mesoderm development (Mesd) deletion interval on mouse chromosome 7, is essential for specification of embryonic polarity and mesoderm induction. They determined that the patterning and cell differentiation defects observed in Mesd deletion homozygotes result solely from loss of the Mesdc2 gene, and therefore they renamed the gene Mesd.Hsieh et al. (2003) showed that Mesd functions in the endoplasmic reticulum (ER) as a specific chaperone for Lrp5 (603506) and Lrp6 (603507), which in conjunction with frizzled (see603408) are coreceptors for canonical Wnt signal transduction. The authors proposed that disruption of embryonic polarity and mesoderm differentiation in Mesd-deficient embryos likely results from a primary defect in Wnt signaling. However, phenotypic differences between Mesd-deficient and Wnt3 (165330) -/- embryos suggested that Mesd may function on related members of the LDLR family. LDLR family members mediate diverse cellular processes ranging from cargo transport to signaling.

Culi and Mann (2003) described boca, an evolutionarily conserved gene in Drosophila melanogaster that encodes an ER protein homologous to the mouse Mesdc2 protein. They showed that boca is specifically required for the intracellular trafficking of members of the LDLR family. Two LDLRs in flies, arrow (see603507), which is required for wingless signal transduction, and yolkless, which is required for yolk protein uptake during oogenesis, were found to require boca function.Culi and Mann (2003) concluded that boca is an essential component of the wingless pathway but is more generally required for the activities of multiple LDLR family members.

Veltman et al. (2005) identified a patient with an infantile sacrococcygeal teratoma and a constitutional t(12;15)(q13;q25) chromosomal translocation, resulting SENP1 (612157)/MESDC2 fusion gene. Both reciprocal SENP1/MESDC2 (SEME) and MESDC2/SENP1 (MESE) fusion genes were transcribed in tumor-derived cells, and their open reading frames encoded aberrant proteins. In contrast to wildtype MESDC2, the translocation-associated SEME protein was no longer targeted to the endoplasmic reticulum, leading to a presumed loss-of-function as a chaperone for the WNT coreceptors LRP5 (603506) and/or LRP6 (603507). SUMO, a posttranslational modifier, plays an important role in several cellular key processes and is cleaved from its substrates by wildtype SENP1. In vitro studies revealed that translocation-associated MESE proteins exhibited desumoylation capacities similar to those observed for wildtype SENP1.Veltman et al. (2005) speculated that spatiotemporal disturbances in desumoylating activities during critical stages of embryonic development might be responsible for teratoma formation. The constitutional t(12;15)(q13;q25) translocation suggested SENP1 and MESDC2 as candidate genes for neonatal/infantile germ cell tumor development.


Molecular Genetics

In 5 probands with a progressive deforming type of osteogenesis imperfecta (OI20;618644),Moosa et al. (2019) identified homozygous mutations in the MESD gene (607783.0001-607783.0004) for which their unaffected parents were heterozygous. Noting that all 4 patient mutations remove a highly conserved ER-retention domain, the authors suggested that they represent hypomorphic alleles. Using site-directed mutagenesis to modify a mouse Mesd construct, they created a K212X mutant lacking the ER-retention domain, and demonstrated that the mutant retained the ability to chaperone and traffic LRP5 (603506), although it appeared to do so less efficiently than wildtype MESD.

In 3 stillborn sibs with OI20, who were born to nonconsanguineous parents of German origin,Sturznickel et al. (2021) identified compound heterozygous mutations in the MESD gene, the previously identified 5-bp deletion (c.607_611del;607783.0004) and a novel 1-bp deletion (c.265del;607783.0005). Each parent was heterozygous for one of the disease-causing variants. Sequencing of the mRNA from the parents revealed a complete loss of the mRNA harboring the c.265del mutation, while the mRNA with the c.607_611del mutation was readily detected. The authors suggested that the prenatally lethal phenotype in this family was likely related to complete functional loss of one MESD allele, which could not be compensated by the residual function of the second allele.


Animal Model

Wines et al. (2001) identified Mesdc2 within a region of mouse chromosome 7 that, when deleted, results in failure to form mesoderm and embryonic lethality.


ALLELIC VARIANTS (5 Selected Examples):

.0001 OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 1-BP DUP, 632A
  RCV000853610...

In Brazilian girl (patient 1) and an unrelated Brazilian boy (patient 4) from consanguineous families with a progressive deforming type of osteogenesis imperfecta (OI20;618644),Moosa et al. (2019) identified homozygosity for a 1-bp duplication (c.632dupA, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Lys212GlufsTer19) removing a highly conserved ER-retention domain. The unaffected parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The affected girl died at age 17 months of sepsis-associated respiratory failure, whereas the boy was alive but nonambulatory at 12 years of age.


.0002 OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, ARG226TER
  RCV000853611

In a Portuguese boy (patient 3) with a progressive deforming type of osteogenesis imperfecta (OI20;618644),Moosa et al. (2019) identified homozygosity for a c.676C-T transition (c.676C-T, NM_015154.1) in exon 3 of the MESD gene, resulting in an arg226-to-ter (R226X) substitution that removes a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The patient died of respiratory failure at 17 years of age.


.0003 OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 2-BP DEL, NT631
  RCV000853612

In a 10-year-old Turkish boy (patient 2) with a progressive deforming type of osteogenesis imperfecta (OI20;618644),Moosa et al. (2019) identified homozygosity for a 2-bp deletion (c.631_632del, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Lys211GlufsTer19) removing a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. Analysis of patient fibroblasts showed that, in contrast to wildtype MESD, the mutant was not detected in cell lysate, consistent with mutant MESD failing to remain intracellular when the ER-retention domain is lost.


.0004 OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 5-BP DEL, NT607
  RCV000853613

In a Brazilian male infant (patient 5) with a progressive deforming type of osteogenesis imperfecta (OI20;618644),Moosa et al. (2019) identified homozygosity for a 5-bp deletion (c.607_611del, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Thr203AlafsTer26), removing a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The patient died of respiratory failure at age 7 months.

In 3 stillborn sibs with OI20, who were born to nonconsanguineous parents of German origin,Sturznickel et al. (2021) identified compound heterozygous mutations in the MESD gene: the c.607_611del mutation in exon 3, and a 1-bp deletion (c.265delG;607783.0005) in exon 2, resulting in a frameshift and premature termination (Ala89HisfsTer8). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Sequencing of the mRNA from the parents revealed a complete loss of the mRNA harboring the c.265del mutation, while the mRNA with the c.607_611del mutation was readily detected.Sturznickel et al. (2021) suggested that the prenatally lethal phenotype in this family was likely related to complete functional loss of one MESD allele, which could not be compensated by the residual function of the second allele.


.0005 OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 1-BP DEL, 265G
  RCV003152498

For discussion of the 1-bp deletion (c.265delG) in exon 2 of the MESD gene, resulting in a frameshift and premature termination (Ala89HisfsTer8), that was found in compound heterozygous state in 3 stillborn sibs with osteogenesis imperfecta type XX (OI20;618644) bySturznickel et al. (2021), see607783.0004.


REFERENCES

  1. Culi, J., Mann, R. S.Boca, an endoplasmic reticulum protein required for Wingless signaling and trafficking of LDL receptor family members in Drosophila. Cell 112: 343-354, 2003. [PubMed:12581524,related citations] [Full Text]

  2. Gross, M. B.Personal Communication. Baltimore, Md. 10/15/2019.

  3. Hsieh, J.-C., Lee, L., Zhang, L., Wefer, S., Brown, K., DeRossi, C., Wines, M. E., Rosenquist, T., Holdener, B. C.Mesd encodes the LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 112: 355-367, 2003. [PubMed:12581525,related citations] [Full Text]

  4. Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C.-A., and 21 others.Autosomal-recessive mutations in MESD cause osteogenesis imperfecta. Am. J. Hum. Genet. 105: 836-843, 2019. [PubMed:31564437,images,related citations] [Full Text]

  5. Nagase, T, Miyajima, N, Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa, K., Kawarabayashi, Y., Kotani, H., Nomura, N.Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 37-43, 1995. [PubMed:7788527,related citations] [Full Text]

  6. Sturznickel, J., Jahn-Rickert, K., Zustin, J., Hennig, F., Delsmann, M. M., Schoner, K., Rehder, H., Kreczy, A., Schinke, T., Amling, M., Kornak, U., Oheim, R.Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX. J. Bone Miner. Res. 36: 1077-1087, 2021. [PubMed:33596325,related citations] [Full Text]

  7. Veltman, I. M., Vreede, L. A., Cheng, J., Looijenga, L. H. J., Janssen, B., Schoenmakers, E. F. P. M., Yeh, E. T. H., Geurts van Kessel, A.Fusion of the SUMO/sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25). Hum. Molec. Genet. 14: 1955-1963, 2005. [PubMed:15917269,related citations] [Full Text]

  8. Wines, M. E., Lee, L., Katari, M. S., Zhang, L., DeRossi, C., Shi, Y., Perkins, S., Feldman, M., McCombie, W. R., Holdener, B. C.Identification of mesoderm development (mesd) candidate genes by comparative mapping and genome sequence analysis. Genomics 72: 88-98, 2001. [PubMed:11247670,related citations] [Full Text]


Sonja A. Rasmussen - updated : 01/31/2023
Marla J. F. O'Neill - updated : 10/25/2019
Matthew B. Gross - updated : 10/15/2019
Patricia A. Hartz : 10/9/2013
George E. Tiller - updated : 11/17/2008
Matthew B. Gross - updated : 5/13/2003
Creation Date:
Stylianos E. Antonarakis : 5/13/2003
carol : 01/31/2023
alopez : 10/25/2019
carol : 10/16/2019
mgross : 10/15/2019
mgross : 10/18/2013
tpirozzi : 10/9/2013
wwang : 11/18/2008
wwang : 11/17/2008
mgross : 5/13/2003
mgross : 5/13/2003

* 607783

MESODERM DEVELOPMENT LRP CHAPERONE; MESD


Alternative titles; symbols

MESODERM DEVELOPMENT CANDIDATE GENE 2; MESDC2
MESODERM DEVELOPMENT GENE
KIAA0081
BOCA, DROSOPHILA, HOMOLOG OF; BOCA


Other entities represented in this entry:

MESDC2/SENP1 FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: MESD

Cytogenetic location: 15q25.1   Genomic coordinates(GRCh38) : 15:80,946,289-80,989,819(from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q25.1 Osteogenesis imperfecta, type XX 618644 Autosomal recessive 3

TEXT

Cloning and Expression

By sequencing cDNAs randomly selected from a cDNA library derived from the human immature myeloid cell line KG-1, Nagase et al. (1995) isolated a cDNA encoding MESDC2, which they designated KIAA0081. The predicted 233-amino acid protein contains at least 1 putative transmembrane region. Northern blot analysis detected expression in all tissues tested except peripheral blood leukocytes.

Wines et al. (2001) cloned mouse Mesdc2, which encodes a 223-amino acid protein that shares 82% identity with the 234-amino acid human protein. MESDC2 was predicted to have an N-terminal transmembrane domain. Northern blot analysis detected a 1.8-kb transcript in mouse embryos throughout development and in all adult mouse tissues tested, except skeletal muscle.


Mapping

Nagase et al. (1995) mapped the MESDC2 gene to chromosome 15 by analysis of human-rodent hybrid cell lines.

By radiation hybrid analysis and sequencing a BAC contig, Wines et al. (2001) mapped the MESCD2 gene to chromosome 15q23-q25. They mapped the mouse Mesdc2 gene to a region of chromosome 7 that shares homology of synteny with human chromosome 15q23-q25.

Veltman et al. (2005) stated that the MESDC2 gene maps to chromosome 15q25.

Gross (2019) mapped the MESD gene to chromosome 15q25.1 based on an alignment of the MESD sequence (GenBank BC009210) with the genomic sequence (GRCh38).


Gene Function

Hsieh et al. (2003) demonstrated that Mesdc2, a gene identified in the mesoderm development (Mesd) deletion interval on mouse chromosome 7, is essential for specification of embryonic polarity and mesoderm induction. They determined that the patterning and cell differentiation defects observed in Mesd deletion homozygotes result solely from loss of the Mesdc2 gene, and therefore they renamed the gene Mesd. Hsieh et al. (2003) showed that Mesd functions in the endoplasmic reticulum (ER) as a specific chaperone for Lrp5 (603506) and Lrp6 (603507), which in conjunction with frizzled (see 603408) are coreceptors for canonical Wnt signal transduction. The authors proposed that disruption of embryonic polarity and mesoderm differentiation in Mesd-deficient embryos likely results from a primary defect in Wnt signaling. However, phenotypic differences between Mesd-deficient and Wnt3 (165330) -/- embryos suggested that Mesd may function on related members of the LDLR family. LDLR family members mediate diverse cellular processes ranging from cargo transport to signaling.

Culi and Mann (2003) described boca, an evolutionarily conserved gene in Drosophila melanogaster that encodes an ER protein homologous to the mouse Mesdc2 protein. They showed that boca is specifically required for the intracellular trafficking of members of the LDLR family. Two LDLRs in flies, arrow (see 603507), which is required for wingless signal transduction, and yolkless, which is required for yolk protein uptake during oogenesis, were found to require boca function. Culi and Mann (2003) concluded that boca is an essential component of the wingless pathway but is more generally required for the activities of multiple LDLR family members.

Veltman et al. (2005) identified a patient with an infantile sacrococcygeal teratoma and a constitutional t(12;15)(q13;q25) chromosomal translocation, resulting SENP1 (612157)/MESDC2 fusion gene. Both reciprocal SENP1/MESDC2 (SEME) and MESDC2/SENP1 (MESE) fusion genes were transcribed in tumor-derived cells, and their open reading frames encoded aberrant proteins. In contrast to wildtype MESDC2, the translocation-associated SEME protein was no longer targeted to the endoplasmic reticulum, leading to a presumed loss-of-function as a chaperone for the WNT coreceptors LRP5 (603506) and/or LRP6 (603507). SUMO, a posttranslational modifier, plays an important role in several cellular key processes and is cleaved from its substrates by wildtype SENP1. In vitro studies revealed that translocation-associated MESE proteins exhibited desumoylation capacities similar to those observed for wildtype SENP1. Veltman et al. (2005) speculated that spatiotemporal disturbances in desumoylating activities during critical stages of embryonic development might be responsible for teratoma formation. The constitutional t(12;15)(q13;q25) translocation suggested SENP1 and MESDC2 as candidate genes for neonatal/infantile germ cell tumor development.


Molecular Genetics

In 5 probands with a progressive deforming type of osteogenesis imperfecta (OI20; 618644), Moosa et al. (2019) identified homozygous mutations in the MESD gene (607783.0001-607783.0004) for which their unaffected parents were heterozygous. Noting that all 4 patient mutations remove a highly conserved ER-retention domain, the authors suggested that they represent hypomorphic alleles. Using site-directed mutagenesis to modify a mouse Mesd construct, they created a K212X mutant lacking the ER-retention domain, and demonstrated that the mutant retained the ability to chaperone and traffic LRP5 (603506), although it appeared to do so less efficiently than wildtype MESD.

In 3 stillborn sibs with OI20, who were born to nonconsanguineous parents of German origin, Sturznickel et al. (2021) identified compound heterozygous mutations in the MESD gene, the previously identified 5-bp deletion (c.607_611del; 607783.0004) and a novel 1-bp deletion (c.265del; 607783.0005). Each parent was heterozygous for one of the disease-causing variants. Sequencing of the mRNA from the parents revealed a complete loss of the mRNA harboring the c.265del mutation, while the mRNA with the c.607_611del mutation was readily detected. The authors suggested that the prenatally lethal phenotype in this family was likely related to complete functional loss of one MESD allele, which could not be compensated by the residual function of the second allele.


Animal Model

Wines et al. (2001) identified Mesdc2 within a region of mouse chromosome 7 that, when deleted, results in failure to form mesoderm and embryonic lethality.


ALLELIC VARIANTS5 Selected Examples):

.0001   OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 1-BP DUP, 632A
SNP: rs745891632, gnomAD: rs745891632, ClinVar: RCV000853610, RCV003768633

In Brazilian girl (patient 1) and an unrelated Brazilian boy (patient 4) from consanguineous families with a progressive deforming type of osteogenesis imperfecta (OI20; 618644), Moosa et al. (2019) identified homozygosity for a 1-bp duplication (c.632dupA, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Lys212GlufsTer19) removing a highly conserved ER-retention domain. The unaffected parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The affected girl died at age 17 months of sepsis-associated respiratory failure, whereas the boy was alive but nonambulatory at 12 years of age.


.0002   OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, ARG226TER
SNP: rs1021282486, gnomAD: rs1021282486, ClinVar: RCV000853611

In a Portuguese boy (patient 3) with a progressive deforming type of osteogenesis imperfecta (OI20; 618644), Moosa et al. (2019) identified homozygosity for a c.676C-T transition (c.676C-T, NM_015154.1) in exon 3 of the MESD gene, resulting in an arg226-to-ter (R226X) substitution that removes a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The patient died of respiratory failure at 17 years of age.


.0003   OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 2-BP DEL, NT631
SNP: rs745891632, gnomAD: rs745891632, ClinVar: RCV000853612

In a 10-year-old Turkish boy (patient 2) with a progressive deforming type of osteogenesis imperfecta (OI20; 618644), Moosa et al. (2019) identified homozygosity for a 2-bp deletion (c.631_632del, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Lys211GlufsTer19) removing a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. Analysis of patient fibroblasts showed that, in contrast to wildtype MESD, the mutant was not detected in cell lysate, consistent with mutant MESD failing to remain intracellular when the ER-retention domain is lost.


.0004   OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 5-BP DEL, NT607
SNP: rs780491808, gnomAD: rs780491808, ClinVar: RCV000853613

In a Brazilian male infant (patient 5) with a progressive deforming type of osteogenesis imperfecta (OI20; 618644), Moosa et al. (2019) identified homozygosity for a 5-bp deletion (c.607_611del, NM_015154.1) in exon 3 of the MESD gene, causing a frameshift predicted to result in a premature termination codon (Thr203AlafsTer26), removing a highly conserved ER-retention domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not a common polymorphism in the Exome Variant Server, 1000 Genomes Project, dbSNP, ExAC, or gnomAD databases. The patient died of respiratory failure at age 7 months.

In 3 stillborn sibs with OI20, who were born to nonconsanguineous parents of German origin, Sturznickel et al. (2021) identified compound heterozygous mutations in the MESD gene: the c.607_611del mutation in exon 3, and a 1-bp deletion (c.265delG; 607783.0005) in exon 2, resulting in a frameshift and premature termination (Ala89HisfsTer8). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Sequencing of the mRNA from the parents revealed a complete loss of the mRNA harboring the c.265del mutation, while the mRNA with the c.607_611del mutation was readily detected. Sturznickel et al. (2021) suggested that the prenatally lethal phenotype in this family was likely related to complete functional loss of one MESD allele, which could not be compensated by the residual function of the second allele.


.0005   OSTEOGENESIS IMPERFECTA, TYPE XX

MESD, 1-BP DEL, 265G
SNP: rs759048290, gnomAD: rs759048290, ClinVar: RCV003152498

For discussion of the 1-bp deletion (c.265delG) in exon 2 of the MESD gene, resulting in a frameshift and premature termination (Ala89HisfsTer8), that was found in compound heterozygous state in 3 stillborn sibs with osteogenesis imperfecta type XX (OI20; 618644) by Sturznickel et al. (2021), see 607783.0004.


REFERENCES

  1. Culi, J., Mann, R. S.Boca, an endoplasmic reticulum protein required for Wingless signaling and trafficking of LDL receptor family members in Drosophila. Cell 112: 343-354, 2003. [PubMed: 12581524] [Full Text: https://doi.org/10.1016/s0092-8674(02)01279-5]

  2. Gross, M. B.Personal Communication. Baltimore, Md. 10/15/2019.

  3. Hsieh, J.-C., Lee, L., Zhang, L., Wefer, S., Brown, K., DeRossi, C., Wines, M. E., Rosenquist, T., Holdener, B. C.Mesd encodes the LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 112: 355-367, 2003. [PubMed: 12581525] [Full Text: https://doi.org/10.1016/s0092-8674(03)00045-x]

  4. Moosa, S., Yamamoto, G. L., Garbes, L., Keupp, K., Beleza-Meireles, A., Moreno, C. A., Valadares, E. R., de Sousa, S. B., Maia, S., Saraiva, J., Honjo, R. S., Kim, C.-A., and 21 others.Autosomal-recessive mutations in MESD cause osteogenesis imperfecta. Am. J. Hum. Genet. 105: 836-843, 2019. [PubMed: 31564437] [Full Text: https://doi.org/10.1016/j.ajhg.2019.08.008]

  5. Nagase, T, Miyajima, N, Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa, K., Kawarabayashi, Y., Kotani, H., Nomura, N.Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 37-43, 1995. [PubMed: 7788527] [Full Text: https://doi.org/10.1093/dnares/2.1.37]

  6. Sturznickel, J., Jahn-Rickert, K., Zustin, J., Hennig, F., Delsmann, M. M., Schoner, K., Rehder, H., Kreczy, A., Schinke, T., Amling, M., Kornak, U., Oheim, R.Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX. J. Bone Miner. Res. 36: 1077-1087, 2021. [PubMed: 33596325] [Full Text: https://doi.org/10.1002/jbmr.4277]

  7. Veltman, I. M., Vreede, L. A., Cheng, J., Looijenga, L. H. J., Janssen, B., Schoenmakers, E. F. P. M., Yeh, E. T. H., Geurts van Kessel, A.Fusion of the SUMO/sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25). Hum. Molec. Genet. 14: 1955-1963, 2005. [PubMed: 15917269] [Full Text: https://doi.org/10.1093/hmg/ddi200]

  8. Wines, M. E., Lee, L., Katari, M. S., Zhang, L., DeRossi, C., Shi, Y., Perkins, S., Feldman, M., McCombie, W. R., Holdener, B. C.Identification of mesoderm development (mesd) candidate genes by comparative mapping and genome sequence analysis. Genomics 72: 88-98, 2001. [PubMed: 11247670] [Full Text: https://doi.org/10.1006/geno.2000.6466]


Contributors:
Sonja A. Rasmussen - updated : 01/31/2023
Marla J. F. O'Neill - updated : 10/25/2019
Matthew B. Gross - updated : 10/15/2019
Patricia A. Hartz : 10/9/2013
George E. Tiller - updated : 11/17/2008
Matthew B. Gross - updated : 5/13/2003

Creation Date:
Stylianos E. Antonarakis : 5/13/2003

Edit History:
carol : 01/31/2023
alopez : 10/25/2019
carol : 10/16/2019
mgross : 10/15/2019
mgross : 10/18/2013
tpirozzi : 10/9/2013
wwang : 11/18/2008
wwang : 11/17/2008
mgross : 5/13/2003
mgross : 5/13/2003



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® 1966-2025 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® 1966-2025 Johns Hopkins University.
Printed: Nov. 28, 2025

OMIM Donation:

Dear OMIM User,

To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.

Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM


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