SMAD4 -- Juvenile polyposis syndrome, (MIM 174900)
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:6770
Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for juvenile polyposis syndrome (typical JPS) and 15 were suspected to have JPS. Using MLPA, large genomic deletions involving the SMAD4 were found in six (9%) patients with typical JPS. Four exhibited a heterozygous deletion of all SMAD4 probes encompassing the entire SMAD4 gene and the promoter region. One patient had a deletion of coding exons 5-11 and another had a deletion of coding exons 6-11. All deletions were confirmed in a second independent MLPA test.
Aretz et al, 2007, PMID 17873119
Archival material of 29 patients with JPS from 27 families was collected. MLPA identified a germline hemizygous large genomic deletion involving SMAD4 in a one patient.
Van Hattem et al, 2008, PMID 18178612
DNA was extracted from 102 JPS probands. By MLPA, one proband had deletion of most of SMAD4 and another deletion of the 5' end of SMAD4.
Calva-Cerqueira et al, 2009, PMID 18823382
Literature Review:
OMIM: https://www.omim.org/entry/174900 (and 600993)
GENEREVIEWS: https://www.ncbi.nlm.nih.gov/books/NBK1469/
Mechanism
Although SMAD4 is a tumor suppressor gene, loss of heterozygosity has not been demonstrated definitively as causal in the development of polyps. Furthermore, whether such changes would affect cells in the epithelium, the lamina propria, or both is also not known. SMAD4 is the common intracellular mediator of the TGF-β superfamily signaling pathways. BMPR1A is a type I cell surface receptor for the BMP pathway. Ligands, such as TGF-β or BMP, bind to a receptor and activate signaling pathways leading to protein complexes that migrate to the nucleus and bind directly to DNA sequences to regulate transcription [Heldin et al 1997]. The downstream genes under the control of these signaling pathways are still being actively investigated.
Pathogenic variants.
. See Table 5. Germline pathogenic variants have been described in all eleven coding exons. Changes include small deletions, insertions, and missense and nonsense pathogenic variants. Two splice site variants have been reported. Most pathogenic variants are unique, but three have been reported in multiple unrelated families: c.1244_1247delACAG, c.1162C>T, and p.Arg361Cys. See Howe et al [2004] and Calva-Cerqueira et al [2009] for a comprehensive list of the pathogenic variants reported in SMAD4 (previously known as MADH4). Larger deletions of SMAD4 may also occur in up to 4% of affected individuals [Aretz et al 2007, van Hattem et al 2008, Calva-Cerqueira et al 2009]. Deletions and pathogenic missense variants have also been reported in the promoter region [Calva-Cerqueira et al 2010].
Abnormal gene product.
The MH1 domain of the SMAD4 protein can directly bind to the DNA of target genes. Pathogenic variants in this domain can significantly reduce the DNA binding activity of SMAD4. Most pathogenic variants, including the three recurrent pathogenic variants in Table 5, occur in the MH2 domain, which plays an important role for nuclear localization, interaction with other MAD proteins, and transcriptional activation. In vitro studies demonstrate that pathogenic nonsense variants lead to significantly reduced bone morphogenetic protein signaling, with less of an effect for missense variants [Carr et al 2012].
Overall, frameshift, nonsense, and missense variants accounted for the majority of pathogenic SMAD4 (72.9%) and BMPR1A (61.8%) alterations in the ECS as well as the LBSB group (SMAD4: 79.9%; BMPR1A: 70.8%; Supplementary Table 3). Only large genomic, i.e., single or multiexon deletions in SMAD4 were significantly overrepresented in the ECS compared with the LBSB group. Splice site variants were noted in 4-6% of SMAD4 and 10-16% of BMPAR1A
Blatter et al, 2020, PMID: 32398773
Pilot application of harmonised terms:
Inheritance:
Autosomal Dominant
Allelic requirement:
Monoallelic_aut
Disease associated variant consequences:
*Decreased gene product level
Absent gene product
Altered gene product structure
Narrative summary of molecular mechanisms:
SMAD4 is a tumour suppression gene and has a role in common intracellular mediator of the TGF-β superfamily signalling. The molecular mechanism of disease in relation to Juvenile polyposis is felt to be loss of function principally due to reduced or absent DNA binding activity in SMAD4. Variant classes include small and large deletions, insertions, missense, nonsense, splice site and deletion/missense in the promotor region. Of note, activating (gain of function) heterozygous de novo mutations in the MH2 domain (principally reported to affect residues 496 and 500 in the SMAD4 gene) cause Myhre syndrome.
List variant classes in this gene proven to cause this disease:
Stop_gained
missense
Frameshift_variant
Splice_acceptor_variant
Splice_donor_variant
regulatory_region_variant (deletions/missense in promotor region)
Potential novel variant classes based on predicted functional consequence
splice_region_variant
(splice_acceptor_variant predicted to undergo NMD)
(splice_acceptor_variant predicted to escape NMD)
(splice_donor_variant predicted to undergo NMD)
(splice_donor_variant predicted to escape NMD)
start_lost
(frameshift_variant predicted to undergo NMD)
(frameshift_variant predicted to escape NMD)
(stop_gained predicted to undergo NMD)
(stop_gained predicted to escape NMD)
stop_lost
inframe_insertion
inframe_deletion
(gain of upstream Start [uORF])
(gain of upstream Start [oORF])
(Stop lost [uORF])
(Stop lost [oORF])
(Start lost [uORF])
(Frameshift [uORF])
(Frameshift [oORF])
(Stop gained [uORF])
Not included
synonymous_variant
intron_variant
intergenic_variant
3_prime_UTR_variant
5_prime_UTR_variant