Alternative titles; symbols
HGNC Approved Gene Symbol: LTBP3
SNOMEDCT: 716195006;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,538,559-65,558,359 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Dental anomalies and short stature | 601216 | Autosomal recessive | 3 |
| Geleophysic dysplasia 3 | 617809 | Autosomal dominant | 3 |
Transforming growth factors (TGFs) beta-1 (190180), beta-2 (190220), beta-3 (190230), and others have both stimulatory and inhibitory effects on the growth of different cell types and play a role in the production and degradation of the extracellular matrix. TGF-beta molecules are secreted in the form of latent large molecular mass complexes that contain other proteins, such as latent TGF-beta-1 binding protein (LTBP1; 150390). There is evidence that these binding proteins modulate TGF-beta bioavailability.
See Oklu and Hesketh (2000) for a review of the LTBP gene family.
Yin et al. (1995) cloned a novel mouse gene, designated Ltbp3, isolated because of structural similarities to fibrillin (134797). Its 4.6-kb transcript was found to encode a protein sequence related to LTBP1.
Using in situ hybridization, Huckert et al. (2015) analyzed mouse embryos at embryonic day (E) 14.5, E16.5, and E18.5, and observed Ltpb3 expression in various developing bones undergoing either endochondral or intramembranous ossification, including vertebrae, mandibular bone, and base of skull. Expression was also detected in the ventricular and subventricular zones of developing brain vesicles, and in cells surrounding the lumen of the neural tube. Discrete expression was observed in the developing inner ear (cochlea), as well as in the small and large intestine, with the most conspicuous expression at the base of the intestinal crypts. Discrete expression was also observed in the heart outflow tract and in the walls of large blood vessels such as the aorta and pulmonary artery. Huckert et al. (2015) also investigated Ltbp3 expression during tooth development, observing transcripts in cap-stage teeth of mice at E14.5 and in the epithelial and mesenchymal compartments of bell-stage teeth at E16.5, especially in the most differentiated areas, such as the molar cusp tips and the rostral part of the incisors. At E18.5, labeling was seen in differentiating ameloblasts and odontoblasts, with transcripts scattered at the apical secretory pole of ameloblasts.
Li et al. (1995) assigned the human and mouse LTBP3 loci (called LTBP2 and Ltbp2 by them) to regions of conserved synteny on human chromosome 11 and mouse chromosome 19. By PCR analysis of somatic cell hybrid DNA and fluorescence in situ hybridization (FISH), the genes were mapped to human 11q12 and mouse chromosome 19B.
Sawicki et al. (1997) identified the sequence of the human LTBP3 gene on a transcript map encompassing the locus for MEN I (MEN1; 131100) on chromosome 11q13.
Dental Anomalies and Short Stature
In affected members of a consanguineous Pakistani family with selective tooth agenesis and short stature (DASS; 601216), Noor et al. (2009) identified a homozygous nonsense mutation in the LTBP3 gene (Y744X; 602090.0001). Two affected males were examined in detail. The phenotype was characterized by absence of many of the permanent teeth, as well as apparent increased bone density in the spine and skull base. The findings suggested an important role for LTBP3-mediated transcription in development of the axial skeleton.
In 2 Emirati sisters with complete agenesis of permanent dentition and short stature, Dugan et al. (2015) sequenced the LTBP3 gene and identified homozygosity for a 1-bp insertion (602090.0002).
In 4 families segregating autosomal recessive amelogenesis imperfecta, short stature, and variable degrees of platyspondyly, Huckert et al. (2015) identified biallelic mutations in the LTBP3 gene in all affected individuals (602090.0003-602090.0007). None of the mutations, which segregated with disease in the respective families, were found in the Exome Variant Server or 1000 Genomes Project databases.
In affected individuals from 2 unrelated families with DASS and aneurysmal aortic and arterial disease, Guo et al. (2018) identified homozygous or compound heterozygous mutations in the LTBP3 gene (see, e.g., 602090.0011-602090.0012). In 1 of the families, some heterozygous individuals developed aneurysmal disease at older ages, and in a cohort of 338 sporadic patients with nonsyndromic thoracic aortic dissections, the authors detected heterozygous LTBP3 rare variants in 9 patients. Guo et al. (2018) concluded that biallelic mutations in LTBP3 are associated with risk for thoracic aortic aneurysms and dissections and other arterial aneurysms, in addition to the previously reported skeletal and dental defects, whereas heterozygous LTBP3 mutations might be associated with increased risk for later-onset thoracic aortic disease.
Geleophysic Dysplasia 3
In a mother and her 2 sons who showed features consistent with mild geleophysic dysplasia (GPHYSD3; 617809), McInerney-Leo et al. (2016) identified heterozygosity for a missense mutation in the LTBP3 gene (S696C; 602090.0008). In 2 unrelated boys diagnosed with geleophysic dysplasia, who died in early childhood from respiratory failure, McInerney-Leo et al. (2016) identified heterozygosity for a stop-loss mutation (602090.0009) and a splice site mutation (602090.0010) in LTBP3, respectively.
The official designation for the gene mapped to human chromosome 11 by Li et al. (1995) is LTBP3. An LTBP gene mapped to chromosome 14 and previously designated LTBP3 in the literature is symbolized LTBP2; see 602091.
Dabovic et al. (2002) created an Ltbp3-null mutation in the mouse by gene targeting. Mice homozygous for the mutation developed craniofacial malformations by day 10. At 2 months, there was a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Between 6 and 9 months of age, mutant mice also developed osteosclerosis and osteoarthritis. The pathologic changes were consistent with perturbed TGF-beta (190180) signaling in the skull and long bones.
Using direct lineage tracing and loss-of-function studies in zebrafish, Zhou et al. (2011) demonstrated that Ltbp3 transcripts mark a field of cardiac progenitor cells with defining characteristics of the anterior second heart field in mammals. Specifically, Ltbp3+ cells differentiate in pharyngeal mesoderm after formation of the heart tube, elongate the heart tube at the outflow pole, and give rise to 3 cardiovascular lineages in the outflow tract and myocardium in the distal ventricle. In addition to expressing Ltbp3, a protein that regulates the bioavailability of TGF-beta ligands, zebrafish second heart field cells coexpress nkx2.5 (600584), an evolutionarily conserved marker of cardiac progenitor cells in both fields. Embryos devoid of ltbp3 lacked the same cardiac structures derived from ltbp3+ cells due to compromised progenitor proliferation. Furthermore, small molecule inhibition of TGF-beta signaling phenocopied the ltbp3-morphant phenotype whereas expression of a constitutively active TGF-beta type I receptor rescued it. Zhou et al. (2011) concluded that their results uncovered a requirement for ltbp3-TGF-beta signaling during zebrafish second heart field development, a process that serves to enlarge the single ventricular chamber in this species.
In Ltbp3 -/- mice, Huckert et al. (2015) observed enamel defects, with very thin to absent enamel in both incisors and molars, as well as relative class III mandibular prognathism due to maxillary underdevelopment. Histologic analysis of continuously growing incisor enamel organ revealed a mostly cohesive but occasionally nonpalisadic ameloblast layer facing a thinner disorganized enamel matrix, which confirmed amelogenic dysfunction at the cellular level.
In affected members of a consanguineous Pakistani family with selective tooth agenesis and short stature (DASS; 601216), Noor et al. (2009) identified a homozygous 2322C-G transversion in the LTBP3 gene, resulting in a tyr744-to-ter (Y744X) substitution. PCR analysis showed decreased mutant mRNA levels, consistent with nonsense-mediated mRNA decay. The mutation was not identified in 240 Pakistani controls.
In 2 Emirati sisters with complete agenesis of permanent dentition and short stature (DASS; 601216), who also exhibited mitral valve prolapse with mild insufficiency, Dugan et al. (2015) identified homozygosity for a 1-bp insertion (c.1858_1859insG, NM_021070.4) in exon 13 of the LTBP3 gene, causing a frameshift predicted to result in premature termination after 171 amino acids (Cys620TrpfsTer171). Analysis by real-time quantitative PCR indicated that nonsense-mediated decay was not significant and that truncated LTBP3, lacking 12 of 15 functional EGF (131530) domains, would be generated. The mutation was present in heterozygosity in the unaffected father; the unaffected mother and brothers were unavailable for study.
In 2 Turkish sisters with amelogenesis imperfecta and short stature (DASS; 601216), who also exhibited generalized platyspondyly, Huckert et al. (2015) identified homozygosity for a 14-bp deletion (c.2071_2084delTACCGGCTCAAAGC, NM_001130144.2) in exon 14 of the LTBP3 gene, causing a frameshift predicted to result in a prematurely terminated protein (Tyr691LeufsTer95) lacking the terminal 612 amino acids, including the EGF (131530)-like, TB, EGF-like calcium-binding, and IGF (147440)-binding domains. The mutation, which was located within a zone of homozygosity shared by the 2 affected sibs but not present in their unaffected brother or parents, was not found in the Exome Variant Server or 1000 Genomes Project databases. The 14-bp deletion did not appear to result in nonsense-medicated decay, as it was present in RNA extracted from a patient gingival biopsy.
In a French sister and brother with amelogenesis imperfecta and short stature (DASS; 601216), who also exhibited mild platyspondyly, Huckert et al. (2015) identified compound heterozygosity for a c.421C-T transition (c.421C-T, NM_001130144.2) in exon 2 of the LTBP3 gene, resulting in a gln141-to-ter (Q141X) substitution, and a splice site mutation (c.1531+1G-T; 602090.0005) in intron 8, predicted to cause in-frame skipping of exon 8. Their unaffected parents were unavailable for study. Neither mutation was found in the Exome Variant Server or 1000 Genomes Project databases.
For discussion of the splice site mutation (c.1531+1G-T, NM_001130144.2) in the LTBP3 gene that was found in compound heterozygous state in sibs with amelogenesis imperfecta and short stature (DASS; 601216) by Huckert et al. (2015), see 602090.0004.
In a 12-year-old Brazilian boy with amelogenesis imperfecta and short stature (DASS; 601216), who was originally described by Bertola et al. (2009) and who also exhibited delayed eruption of dentition and mild platyspondyly, Huckert et al. (2015) identified homozygosity for a 1-bp deletion (c.2216_2217delG, NM_001130144.2) in exon 15 of the LTBP3 gene, causing a frameshift predicted to result in a premature termination codon (Gly739AlafsTer7). The deletion, which segregated with disease in the family, was not found in the Exome Variant Server or 1000 Genomes Project databases.
In 3 Pakistani sibs with amelogenesis imperfecta and short stature (DASS; 601216), who also exhibited oligodontia, generalized platyspondyly, and scoliosis, Huckert et al. (2015) identified homozygosity for a 1-bp deletion (c.2356_2357delG, NM_001130144.2) in exon 17 of the LTBP3 gene, causing a frameshift predicted to result in a premature termination codon (Val786TrpfsTer82). The mutation, which segregated with disease in the family, was not found in the Exome Variant Server or 1000 Genomes Project databases.
In a mother (SKDP-4.2) and 2 sons (SKDP-4.4 and SKDP-4.3) with mild geleophysic dysplasia-3 (GPHYSD3; 617809), McInerney-Leo et al. (2016) identified heterozygosity for a c.2087C-G transversion (c.2087C-G, NM_001130144) in exon 14 of the LTBP3 gene, resulting in a ser696-to-cys (S696C) substitution at a highly conserved residue in an EGF-like calcium-binding domain. The mutation was not found in the 2 of the mother's 5 unaffected sibs who underwent whole-exome sequencing. Patient fibroblasts were disorganized and irregular in size compared to control fibroblasts, but FBN1 (134797) staining intensity and pattern were similar to control.
In a boy (GD-1) with geleophysic dysplasia (GPHYSD3; 617809), who died of respiratory failure at age 4 years, McInerney-Leo et al. (2016) identified heterozygosity for a de novo c.3912A-T transversion (c.3912A-T, NM_001130144.2) in exon 28 of the LTBP3 gene, resulting in loss of the normal stop codon (Ter1304CysExt12). The mutation was not present in his unaffected parents, in 200 ethnically matched controls or 5,483 in-house exomes, or in the ExAC, dbSNP (build 129), or 1000 Genomes Project databases.
In a boy (GD-2) with geleophysic dysplasia (GPHYSD3; 617809), who died of respiratory failure at age 18 months, McInerney-Leo et al. (2016) identified heterozygosity for a de novo splice site mutation (c.1846+5G-A, NM_001130144.2) in intron 12 of the LTBP3 gene. The mutation was not present in his unaffected parents, in 200 ethnically matched controls or 5,483 in-house exomes, or in the ExAC, dbSNP (build 129), or 1000 Genomes Project databases.
In a brother and 2 sisters with dental anomalies and short stature (DASS; 601216), who also exhibited mitral valve prolapse and arterial aneurysmal disease, Guo et al. (2018) identified compound heterozygosity for mutations in the LTBP3 gene: a 1-bp deletion (c.132delG, NM_001130144), causing a frameshift predicted to result in a premature termination codon (Pro45ArgfsTer25), and a c.2248G-T transversion, resulting in a glu750-to-ter (E750X; 602090.0012) substitution. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in the gnomAD database. Both sisters exhibited mild mitral valve prolapse, and 1 sister also had aortic root dilation, whereas their brother had abdominal aortic aneurysm and visceral and peripheral arterial aneurysms.
For discussion of the c.2248G-T transversion (c.2248G-T, NM_001130144) in the LTBP3 gene, resulting in a glu750-to-ter (E750X) substitution, that was found in compound heterozygous state in 3 sibs with dental anomalies and short stature (DASS; 601216) by Guo et al. (2018), see 602090.0011.
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