* 180203

RB TRANSCRIPTIONAL COREPRESSOR-LIKE 2; RBL2


Alternative titles; symbols

RETINOBLASTOMA-LIKE 2
RETINOBLASTOMA-RELATED GENE RB2; RB2
p130


HGNC Approved Gene Symbol: RBL2

Cytogenetic location: 16q12.2     Genomic coordinates (GRCh38): 16:53,434,471-53,491,648 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16q12.2 Brunet-Wagner neurodevelopmental syndrome 619690 AR 3

TEXT

Description

The RBL2 gene encodes a member of the retinoblastoma (RB) family of proteins that mediates gene expression and regulates the cell cycle by direct binding to the E2F family (see, e.g., 189971) of transcription factors, histone deacetylases, and additional factors (summary by Samra et al., 2021).


Cloning and Expression

Mayol et al. (1993) cloned a retinoblastoma-related human gene, referred to as RB2, on the basis of sequence homology of the E1A-binding domain of the RB1 gene (614041). Structural homology with RB1 suggested a possible function of RB2 as a tumor suppressor gene. RBL2 has a molecular mass of about 120 kD.


Gene Function

Kong et al. (2006) found that RBL2 and RINT1 (610089) were essential for telomere length control in human fibroblasts, with loss of either protein leading to longer telomeres. They proposed that RBL2 forms a complex with RAD50 (604040) through RINT1 to block telomerase-independent telomere lengthening.

Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. In contrast, p107 (RBL1; 116957) -/- and p130 -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells.

Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E (see CCNE1; 123837)-CDK2 (116953) pathway, including Cdkn1a (116899), Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.

Samra et al. (2021) noted that RBL2 binds to the E2F4 (600659) transcription factor and functions as a key regulator of cell division. Previous studies in murine cells suggested a role in neuronal differentiation and survival, including senescence.


Gene Structure

Baldi et al. (1996) characterized the organization and 5-prime flanking region of the Rb2, or p130, gene. They determined that the gene contains 22 exons and spans over 50 kb.


Mapping

Yeung et al. (1993) mapped the RBL2 gene to human chromosome 16q12.2 and rat chromosome 19, using fluorescence in situ hybridization and somatic hybrid cell analysis, respectively. Based on known syntenic relationships among human, rat and mouse, the data suggested that the mouse homolog resides on chromosome 8. Deletions of chromosome 16q have been found in several human neoplasms, including breast, ovarian, hepatic, and prostate cancers, which supports the involvement of RB2 in human cancer as a tumor suppressor gene.


Molecular Genetics

In 2 sibs, born of unrelated parents, with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Brunet et al. (2020) identified compound heterozygous putative loss-of-function mutations in the RBL2 gene (180203.0001 and 180203.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In 3 patients from 2 unrelated consanguineous families with BRUWAG syndrome, Samra et al. (2021) identified homozygous loss-of-function mutations in the RBL2 gene (180203.0003 and 180203.0004) that segregated with the disorder in both families. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Detailed studies of fibroblasts derived from patients in family 1 did not reveal abnormal expression of DNA methyltransferases, did not show DNA methylation abnormalities compared to controls, and did not indicate changes in telomere length or growth characteristics, suggesting that the pathogenesis of the disorder is likely due to another specific function of the RBL2 gene.


Animal Model

LeCouter et al. (1998) showed that p130 -/- mice had arrested development and died between embryonic days 11 and 13. Pathology included markedly reduced neurons in the spinal cord and dorsal root ganglia, fewer myocytes, an abnormally thin myocardium, and extensive apoptosis in multiple organs.

Haigis et al. (2006) found that Rb was expressed in all epithelial cells of mouse colon, whereas p107 was expressed predominantly in the lower half of the crypt, and p130 was expressed in the upper portion of the crypt and in the epithelium lining the lumen. Similarly, undifferentiated cells in the mouse small intestinal crypt expressed Rb and p107, whereas differentiated cells in the villi expressed Rb and p130. Conditional deletion of Rb or p130 increased p107 levels, and Rb/p130 double mutants had even higher levels of p107. Although mutating any of these 3 genes singly had little or no effect, loss of Rb and p107 or p130 together produced chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. In Rb/p130 double mutants, this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals.


ALLELIC VARIANTS ( 4 Selected Examples):

.0001 BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, ARG186TER
  
RCV001807545

In 2 sibs, born of unrelated parents, with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Brunet et al. (2020) identified compound heterozygous mutations in the RBL2 gene: a c.556C-T transition (c.556C-T, NM_005611.3) in exon 3, resulting in an arg186-to-ter (R186X) substitution, and an in-frame deletion of exons 13 to 17 (180203.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. The R186X mutation was not present in the gnomAD database, but was found once in the heterozygous state in an in-house database. The in-frame deletion, which affects a highly conserved pocket domain at the C-terminal end, was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function.


.0002 BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, EX13-17 DEL
   RCV001807546

For discussion of the in-frame deletion of exons 13 to 17 of the RBL2 gene that was found in compound heterozygous state in 2 sibs with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690) by Brunet et al. (2020), see 180203.0001.


.0003 BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, 1-BP DUP, 926A (rs1401758241)
  
RCV001807547

In 2 sibs, born of consanguineous Druze parents (family 1) with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Samra et al. (2021) identified a homozygous 1-bp duplication (c.926dupA, NM_005611.3) in the RBL2 gene, resulting in a frameshift and premature termination (Leu310AlafsTer3). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed a significant reduction in mutant transcript levels and lack of protein expression, consistent with a loss of function. Studies of patient fibroblasts were unable to detect abnormalities related to possible functions of the RBL2 gene.


.0004 BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBP2, EX4-5 DEL
   RCV001807548

In an 11-year-old girl, born of consanguineous Kurdish parents (family 2), with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Samra et al. (2021) identified a homozygous out-of-frame deletion of exons 4 and 5 of the RBL2 gene (c.573-1358_766+5del, NM_005611.3). The mutation, which was found by exome sequencing and confirmed by exon-level array, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in premature termination and a loss of function.


REFERENCES

  1. Baldi, A., Boccia, V., Claudio, P. P., De Luca, A., Giordano, A. Genomic structure of the human retinoblastoma-related Rb2/p130 gene. Proc. Nat. Acad. Sci. 93: 4629-4632, 1996. [PubMed: 8643454, related citations] [Full Text]

  2. Brunet, T., Radivojkov-Blagojevic, M., Lichtner, P., Kraus, V., Meitinger, T., Wagner, M. Biallelic loss-of-function variants in RBL2 in siblings with a neurodevelopmental disorder. Ann. Clin. Transl. Neurol. 7: 390-396, 2020. [PubMed: 32105419, images, related citations] [Full Text]

  3. Haigis, K., Sage, J., Glickman, J., Shafer, S., Jacks, T. The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. J. Biol. Chem. 281: 638-647, 2006. [PubMed: 16258171, related citations] [Full Text]

  4. Kong, L.-J., Meloni, A. R., Nevins, J. R. The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Molec. Cell 22: 63-71, 2006. [PubMed: 16600870, related citations] [Full Text]

  5. LeCouter, J. E., Kablar, B., Whyte, P. F. M., Ying, C., Rudnicki, M. A. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development 125: 4669-4679, 1998. [PubMed: 9806916, related citations] [Full Text]

  6. Mayol, X., Grana, X., Baldi, A., Sang, N., Hu, Q., Giordano, A. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 8: 2561-2566, 1993. [PubMed: 8361765, related citations]

  7. Samra, N., Toubiana, S., Yttervik, H., Tzur-Gilat, A., Morani, I., Itzkovich, C., Giladi, L., Abu Jabal, K., Cao, J. Z., Godley, L. A., Mory, A., Baris Feldman, H., Tveten, K., Selig, S., Weiss, K. RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function. J. Hum. Genet. 66: 1101-1112, 2021. [PubMed: 33980986, related citations] [Full Text]

  8. Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., Blelloch, R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genet. 40: 1478-1483, 2008. [PubMed: 18978791, images, related citations] [Full Text]

  9. Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Molec. Cell. Biol. 26: 1170-1182, 2006. [PubMed: 16449633, images, related citations] [Full Text]

  10. Yeung, R. S., Bell, D. W., Testa, J. R., Mayol, X., Baldi, A., Grana, X., Klinga-Levan, K., Knudson, A. G., Giordano, A. The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19. Oncogene 8: 3465-3468, 1993. [PubMed: 8247552, related citations]


Alan F. Scott - updated : 01/19/2022
Cassandra L. Kniffin - updated : 01/04/2022
Patricia A. Hartz - updated : 2/11/2009
Patricia A. Hartz - updated : 9/19/2007
Patricia A. Hartz - updated : 4/27/2006
Rebekah S. Rasooly - updated : 8/6/1998
Creation Date:
Victor A. McKusick : 4/20/1994
carol : 01/19/2022
carol : 01/10/2022
alopez : 01/07/2022
ckniffin : 01/04/2022
carol : 06/17/2011
mgross : 2/16/2009
terry : 2/11/2009
mgross : 10/9/2007
terry : 9/19/2007
mgross : 4/27/2006
terry : 3/16/2005
alopez : 8/6/1998
mimadm : 3/25/1995
carol : 4/20/1994

* 180203

RB TRANSCRIPTIONAL COREPRESSOR-LIKE 2; RBL2


Alternative titles; symbols

RETINOBLASTOMA-LIKE 2
RETINOBLASTOMA-RELATED GENE RB2; RB2
p130


HGNC Approved Gene Symbol: RBL2

Cytogenetic location: 16q12.2     Genomic coordinates (GRCh38): 16:53,434,471-53,491,648 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16q12.2 Brunet-Wagner neurodevelopmental syndrome 619690 Autosomal recessive 3

TEXT

Description

The RBL2 gene encodes a member of the retinoblastoma (RB) family of proteins that mediates gene expression and regulates the cell cycle by direct binding to the E2F family (see, e.g., 189971) of transcription factors, histone deacetylases, and additional factors (summary by Samra et al., 2021).


Cloning and Expression

Mayol et al. (1993) cloned a retinoblastoma-related human gene, referred to as RB2, on the basis of sequence homology of the E1A-binding domain of the RB1 gene (614041). Structural homology with RB1 suggested a possible function of RB2 as a tumor suppressor gene. RBL2 has a molecular mass of about 120 kD.


Gene Function

Kong et al. (2006) found that RBL2 and RINT1 (610089) were essential for telomere length control in human fibroblasts, with loss of either protein leading to longer telomeres. They proposed that RBL2 forms a complex with RAD50 (604040) through RINT1 to block telomerase-independent telomere lengthening.

Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. In contrast, p107 (RBL1; 116957) -/- and p130 -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells.

Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E (see CCNE1; 123837)-CDK2 (116953) pathway, including Cdkn1a (116899), Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.

Samra et al. (2021) noted that RBL2 binds to the E2F4 (600659) transcription factor and functions as a key regulator of cell division. Previous studies in murine cells suggested a role in neuronal differentiation and survival, including senescence.


Gene Structure

Baldi et al. (1996) characterized the organization and 5-prime flanking region of the Rb2, or p130, gene. They determined that the gene contains 22 exons and spans over 50 kb.


Mapping

Yeung et al. (1993) mapped the RBL2 gene to human chromosome 16q12.2 and rat chromosome 19, using fluorescence in situ hybridization and somatic hybrid cell analysis, respectively. Based on known syntenic relationships among human, rat and mouse, the data suggested that the mouse homolog resides on chromosome 8. Deletions of chromosome 16q have been found in several human neoplasms, including breast, ovarian, hepatic, and prostate cancers, which supports the involvement of RB2 in human cancer as a tumor suppressor gene.


Molecular Genetics

In 2 sibs, born of unrelated parents, with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Brunet et al. (2020) identified compound heterozygous putative loss-of-function mutations in the RBL2 gene (180203.0001 and 180203.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In 3 patients from 2 unrelated consanguineous families with BRUWAG syndrome, Samra et al. (2021) identified homozygous loss-of-function mutations in the RBL2 gene (180203.0003 and 180203.0004) that segregated with the disorder in both families. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Detailed studies of fibroblasts derived from patients in family 1 did not reveal abnormal expression of DNA methyltransferases, did not show DNA methylation abnormalities compared to controls, and did not indicate changes in telomere length or growth characteristics, suggesting that the pathogenesis of the disorder is likely due to another specific function of the RBL2 gene.


Animal Model

LeCouter et al. (1998) showed that p130 -/- mice had arrested development and died between embryonic days 11 and 13. Pathology included markedly reduced neurons in the spinal cord and dorsal root ganglia, fewer myocytes, an abnormally thin myocardium, and extensive apoptosis in multiple organs.

Haigis et al. (2006) found that Rb was expressed in all epithelial cells of mouse colon, whereas p107 was expressed predominantly in the lower half of the crypt, and p130 was expressed in the upper portion of the crypt and in the epithelium lining the lumen. Similarly, undifferentiated cells in the mouse small intestinal crypt expressed Rb and p107, whereas differentiated cells in the villi expressed Rb and p130. Conditional deletion of Rb or p130 increased p107 levels, and Rb/p130 double mutants had even higher levels of p107. Although mutating any of these 3 genes singly had little or no effect, loss of Rb and p107 or p130 together produced chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. In Rb/p130 double mutants, this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals.


ALLELIC VARIANTS 4 Selected Examples):

.0001   BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, ARG186TER
SNP: rs2153138545, ClinVar: RCV001807545

In 2 sibs, born of unrelated parents, with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Brunet et al. (2020) identified compound heterozygous mutations in the RBL2 gene: a c.556C-T transition (c.556C-T, NM_005611.3) in exon 3, resulting in an arg186-to-ter (R186X) substitution, and an in-frame deletion of exons 13 to 17 (180203.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. The R186X mutation was not present in the gnomAD database, but was found once in the heterozygous state in an in-house database. The in-frame deletion, which affects a highly conserved pocket domain at the C-terminal end, was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function.


.0002   BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, EX13-17 DEL
ClinVar: RCV001807546

For discussion of the in-frame deletion of exons 13 to 17 of the RBL2 gene that was found in compound heterozygous state in 2 sibs with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690) by Brunet et al. (2020), see 180203.0001.


.0003   BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBL2, 1-BP DUP, 926A ({dbSNP rs1401758241})
SNP: rs1401758241, gnomAD: rs1401758241, ClinVar: RCV001807547

In 2 sibs, born of consanguineous Druze parents (family 1) with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Samra et al. (2021) identified a homozygous 1-bp duplication (c.926dupA, NM_005611.3) in the RBL2 gene, resulting in a frameshift and premature termination (Leu310AlafsTer3). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed a significant reduction in mutant transcript levels and lack of protein expression, consistent with a loss of function. Studies of patient fibroblasts were unable to detect abnormalities related to possible functions of the RBL2 gene.


.0004   BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME

RBP2, EX4-5 DEL
ClinVar: RCV001807548

In an 11-year-old girl, born of consanguineous Kurdish parents (family 2), with Brunet-Wagner neurodevelopmental syndrome (BRUWAG; 619690), Samra et al. (2021) identified a homozygous out-of-frame deletion of exons 4 and 5 of the RBL2 gene (c.573-1358_766+5del, NM_005611.3). The mutation, which was found by exome sequencing and confirmed by exon-level array, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in premature termination and a loss of function.


REFERENCES

  1. Baldi, A., Boccia, V., Claudio, P. P., De Luca, A., Giordano, A. Genomic structure of the human retinoblastoma-related Rb2/p130 gene. Proc. Nat. Acad. Sci. 93: 4629-4632, 1996. [PubMed: 8643454] [Full Text: https://doi.org/10.1073/pnas.93.10.4629]

  2. Brunet, T., Radivojkov-Blagojevic, M., Lichtner, P., Kraus, V., Meitinger, T., Wagner, M. Biallelic loss-of-function variants in RBL2 in siblings with a neurodevelopmental disorder. Ann. Clin. Transl. Neurol. 7: 390-396, 2020. [PubMed: 32105419] [Full Text: https://doi.org/10.1002/acn3.50992]

  3. Haigis, K., Sage, J., Glickman, J., Shafer, S., Jacks, T. The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. J. Biol. Chem. 281: 638-647, 2006. [PubMed: 16258171] [Full Text: https://doi.org/10.1074/jbc.M509053200]

  4. Kong, L.-J., Meloni, A. R., Nevins, J. R. The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Molec. Cell 22: 63-71, 2006. [PubMed: 16600870] [Full Text: https://doi.org/10.1016/j.molcel.2006.02.016]

  5. LeCouter, J. E., Kablar, B., Whyte, P. F. M., Ying, C., Rudnicki, M. A. Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. Development 125: 4669-4679, 1998. [PubMed: 9806916] [Full Text: https://doi.org/10.1242/dev.125.23.4669]

  6. Mayol, X., Grana, X., Baldi, A., Sang, N., Hu, Q., Giordano, A. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 8: 2561-2566, 1993. [PubMed: 8361765]

  7. Samra, N., Toubiana, S., Yttervik, H., Tzur-Gilat, A., Morani, I., Itzkovich, C., Giladi, L., Abu Jabal, K., Cao, J. Z., Godley, L. A., Mory, A., Baris Feldman, H., Tveten, K., Selig, S., Weiss, K. RBL2 bi-allelic truncating variants cause severe motor and cognitive impairment without evidence for abnormalities in DNA methylation or telomeric function. J. Hum. Genet. 66: 1101-1112, 2021. [PubMed: 33980986] [Full Text: https://doi.org/10.1038/s10038-021-00931-z]

  8. Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., Blelloch, R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genet. 40: 1478-1483, 2008. [PubMed: 18978791] [Full Text: https://doi.org/10.1038/ng.250]

  9. Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Molec. Cell. Biol. 26: 1170-1182, 2006. [PubMed: 16449633] [Full Text: https://doi.org/10.1128/MCB.26.4.1170-1182.2006]

  10. Yeung, R. S., Bell, D. W., Testa, J. R., Mayol, X., Baldi, A., Grana, X., Klinga-Levan, K., Knudson, A. G., Giordano, A. The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19. Oncogene 8: 3465-3468, 1993. [PubMed: 8247552]


Contributors:
Alan F. Scott - updated : 01/19/2022
Cassandra L. Kniffin - updated : 01/04/2022
Patricia A. Hartz - updated : 2/11/2009
Patricia A. Hartz - updated : 9/19/2007
Patricia A. Hartz - updated : 4/27/2006
Rebekah S. Rasooly - updated : 8/6/1998

Creation Date:
Victor A. McKusick : 4/20/1994

Edit History:
carol : 01/19/2022
carol : 01/10/2022
alopez : 01/07/2022
ckniffin : 01/04/2022
carol : 06/17/2011
mgross : 2/16/2009
terry : 2/11/2009
mgross : 10/9/2007
terry : 9/19/2007
mgross : 4/27/2006
terry : 3/16/2005
alopez : 8/6/1998
mimadm : 3/25/1995
carol : 4/20/1994