Alternative titles; symbols
HGNC Approved Gene Symbol: LAMB3
SNOMEDCT: 400140006, 724225008, 79855003; ICD10CM: Q81.1;
Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:209,614,870-209,652,425 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.2 | Amelogenesis imperfecta, type IA | 104530 | Autosomal dominant | 3 |
| Epidermolysis bullosa, junctional 1A, intermediate | 226650 | Autosomal recessive | 3 | |
| Epidermolysis bullosa, junctional 1B, severe | 226700 | Autosomal recessive | 3 |
Laminin-5 (LAM5) consists of 3 polypeptides, alpha-3, beta-3, and gamma-2, encoded by the genes LAMA3 (600805), LAMB3, and LAMC2 (150292), respectively.
Pulkkinen et al. (1995) elucidated the exon/intron organization of the human LAMB3 gene. They found that the gene is approximately 29 kb long and consists of 23 exons that vary from 64 to 379 basepairs, accounting for the full-length cDNA with an open reading frame of 3,516 bp encoding 1,172 amino acids. In comparison with the LAMB1 gene, LAMB3 is considerably more compact. This laminin has also been referred to as nicein (125 kD), kalinin (140 kD), and BM600.
Dajee et al. (2003) showed that human keratinocytes lacking laminin-5 and ITGB4 (147557) failed to form tumors on coexpression with RAS (190020) and IKBA (NFKBIA; 164008); however, introduction of wildtype LAMB3 and ITGB4 restored tumor-forming capacity, suggesting that these 2 proteins are required for human squamous cell carcinoma tumorigenesis.
Intermediate Junctional Epidermolysis Bullosa 1A
In a family with nonlethal non-Herlitz type of junctional epidermolysis bullosa (JEB1A; 226650), McGrath et al. (1995) demonstrated compound heterozygosity for a nonsense mutation (150310.0003) and a missense mutation (150310.0006) in the LAMB3 gene.
A number of mutations in the 3 genes that encode the subunit polypeptides of laminin-5--LAMA3, LAMB3, and LAMC2--have been demonstrated in patients with junctional epidermolysis bullosa. The majority of these mutations reside in the LAMB3 gene, which accounts for approximately 80% of all laminin-5 mutations. The predominance of LAMB3 mutations, in comparison with LAMA3 or LAMC2, can be explained, at least in part, by the 2 recurrent hotspot mutations, R635X and R42X. Mutations resulting in premature termination codon translation in both alleles are associated with the Herlitz type of junctional EB, whereas in nonlethal (226650) variants of junctional EB at least one or both alleles have a missense or an in-frame exon-skipping mutation. An exception to this general rule was found by Pulkkinen and Uitto (1998), who reported a woman in her late twenties with a nonlethal form of junctional EB and a 5-bp deletion resulting in a premature termination codon in exon 14 (150310.0010). The mutation was in compound heterozygous state with the common R635X mutation.
Floeth and Bruckner-Tuderman (1999) described a family with severe nonlethal junctional EB (JEB1A; 226650) who had mutations in both the LAMB3 and type XVII collagen (COL17A1; 113811) genes. The index patient was compound heterozygous for 2 mutations in the COL17A1 gene, L855X (113811.0012) and R1226X (113811.0001), and was heterozygous for the R635X mutation in the LAMB3 gene. Absence of collagen XVII and attenuated laminin-5 expression resulted in rudimentary hemidesmosome structure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heterozygotes in this family carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathologic skin phenotype. These observations indicated that the known allelic heterogeneity in junctional EB is further complicated by interactions between unlinked mutations. They also demonstrated that identification of 1 mutation in 1 gene is not sufficient for determination of the genetic basis of junctional EB in a given family.
In 2 unrelated non-Herlitz junctional EB patients with revertant mosaicism, Pasmooij et al. (2007) demonstrated the presence of multiple somatic second-site mutations (see 150310.0012-150310.0016), all correcting the germline mutation E210K (150310.0006).
Severe Junctional Epidermolysis Bullosa 1B
Pulkkinen et al. (1994) found homozygosity for a nonsense mutation (R635X; 150310.0001) in the LAMB3 gene in a patient with Herlitz (severe) junctional epidermolysis bullosa (JEB1B; 226700). Kivirikko et al. (1996) examined 14 families with the lethal (Herlitz) type of junctional EB for mutations in the LAMB3 gene. Premature termination codon mutations were delineated in both alleles of each proband in all pedigrees. In over 50% of the mutant LAMB3 alleles, 2 recurrent mutations, R42X (150310.0003) and R635X, were noted. These nonsense mutations occurred at CpG dinucleotide sequences, suggesting hypermutability of 5-methylcytosine to thymine. Additional evidence suggested that R42X and R635X represent mutation hotspots. Kivirikko et al. (1996) demonstrated inheritance of R635X in a homozygous individual on 2 different genetic backgrounds by haplotype analysis. Furthermore, in 1 family, R42X was shown to be inherited on the maternal allele that lacked this mutation, suggesting that it arose as a result of maternal germline mutation.
Nakano et al. (2000) examined the LAMB3 gene for mutations in 22 Herlitz junctional epidermolysis bullosa families and identified 15 distinct mutations, 8 of them novel, bringing the total number of distinct Herlitz junctional epidermolysis bullosa mutations in LAMB3 to 35. Examination of the LAMB3 mutations in all cases revealed 8 recurrent mutations, 6 of which had previously been reported. The authors noted that the comprehensive Herlitz junctional EB database consisted of a total of 152 mutant alleles in 80 cases, including a set of 111 previously reported alleles from 58 families. R635X (150310.0001) and R42X (150310.0003) were present in 45.4% and 5.9% of the mutant LAMB3 alleles, respectively.
An evolving phenotype with aging is noted in some patients suffering from junctional EB. Gache et al. (2001) studied a patient born with severe junctional EB associated with absent expression of laminin-5. A remarkable reduction of the blistering tendency was observed with aging that correlated with a restored expression of immunoreactive laminin-5 molecules. Genetic analysis of LAMB3 detected compound heterozygosity for the R635X nonsense mutation (150310.0001) and a novel 2-bp deletion (1587delAG; 150310.0011), resulting in a downstream premature termination codon. RT-PCR amplification of total RNA purified from skin biopsies demonstrated that the mutated beta-3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened beta-3 transcript with advancing age. Expression of the mutated beta-3 polypeptide was upregulated in basal keratinocytes with high proliferative potential. Surprisingly, although the N-terminal region of the beta-3 rod domain II was thought to stabilize the tertiary structure of laminin-5, the region was not required for the assembly of the protein, and the mutant laminin-5 retained its adhesive potential. The authors concluded that mRNA rescue may underlie the evolution of the clinical phenotype in inherited skin conditions.
Amelogenesis Imperfecta, Type IA
By whole-exome sequencing in 2 unrelated families of Turkish and Iranian descent, respectively, with autosomal dominant hypoplastic amelogenesis imperfecta (AI1A; 104530), Kim et al. (2013) identified heterozygous truncating mutations in the LAMB3 gene (150310.0017 and 151310.0018) that segregated with the disorder in each family.
In a 4-generation Irish family segregating autosomal dominant hypoplastic amelogenesis imperfecta, Poulter et al. (2014) identified a truncating mutation in the LAMB3 gene (150310.0019) that segregated with the disorder in the family.
Nakano et al. (2002) studied the mutational differences between the Herlitz and non-Herlitz forms of junctional EB. They examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz junctional EB, for mutations in the candidate genes LAMA3, LAMB3, and LAMC2. The largest number of mutations for both forms occurred in the LAMB3 gene. Most cases with Herlitz junctional EB harbored premature termination codon (PTC) mutations in both alleles. In non-Herlitz cases, the PTC mutation was frequently associated with a missense mutation or a putative splicing mutation in trans, i.e., the patient was a compound heterozygote.
Robbins et al. (2001) reasoned that appropriate expression of LAMB3 in junctional epidermolysis bullosa skin could potentially ameliorate the symptoms of the disorder. To explore this therapeutic approach, primary keratinocytes from 6 unrelated junctional EB patients were transduced with a retroviral vector encoding LAMB3 and used to regenerate human skin on severe combined immunodeficient (SCID) mice. Tissue regenerated from LAMB3-transduced junctional EB keratinocytes produced phenotypically normal skin characterized by sustained LAMB3 expression and the formation of hemidesmosomes. Additionally, LAMB3 gene transfer corrected the distribution of a number of important basement membrane zone proteins. Skin produced from LAMB3-negative junctional EB cells mimicked the hallmarks of the disease state and did not exhibit any of the aforementioned traits. Therefore, by effecting therapeutic gene transfer to LAMB3-deficient primary keratinocytes, it is possible to produce healthy, normal skin tissue in vivo. These data supported the utility of gene therapy for junctional EB and highlighted the potential for gene delivery in the treatment of human genetic skin disease.
Severe Junctional Epidermolysis Bullosa 1B
In an infant with the Herlitz form of junctional epidermolysis bullosa (JEB1B; 226700), Pulkkinen et al. (1994) identified a homozygous C-to-T transition in the LAMB3 gene, resulting in an arg635-to-ter (R635X) substitution. Ultrastructural and immunofluorescence antigenic mapping studies demonstrated tissue separation within or just above the level of the lamina lucida. Northern hybridization of keratinocyte mRNA revealed markedly reduced levels of the laminin beta-3 chain mRNA. Both unaffected parents were shown to be heterozygous carriers.
Ashton et al. (1997) assessed the frequency of the R635X mutation in 12 British patients with lethal (Herlitz) junctional EB using PCR amplification of genomic DNA and restriction endonuclease digestion. R635X was found in 7 of 24 (29%) mutant alleles, confirming its relative frequency within the British gene pool. In addition, haplotype analysis using intragenic polymorphisms showed that the mutation arose on at least 4 different haplotype backgrounds, suggesting that it represents a mutation hotspot rather than propagation of a common British ancestral allele. These findings supported the hypermutable nature of this CpG dinucleotide.
In studies of a European cohort of 14 families with the lethal Herlitz type of junctional EB, Pulkkinen et al. (1997) found the R635X mutation in the homozygous state in 4 of the probands and in the heterozygous state in 6 of the probands. In all, LAMB3 mutations accounted for 22 (79%) of 28 junctional EB alleles, and 14 (64%) of 22 LAMB3 alleles harbored the R635X mutation.
In a study of 12 patients with Herlitz junctional EB, Muhle et al. (2005) observed that the 4 patients who survived longer than 6 months were females who were homozygous for R635X. In these 4 patients, disease progression as quantified by the percentage of affected body surface occurred relatively slowly during the first months of life, and they had better initial development and weight gain. However, they all died between 7.5 and 30 months of age. The 1 male patient who was also homozygous for R635X presented with a large skin defect at birth and remained hospitalized because of severe chronic wound infections and failure to thrive until his death at 5 months of age. Muhle et al. (2005) concluded that modifying factors may lead to significant variability in the clinical course of the disease and that other diagnostic means such as immunofluorescence and mRNA analysis should be taken into account when assessing the prognosis of an individual patient.
Intermediate Junctional Epidermolysis Bullosa 1A
In 2 sibs with nonlethal JEB (JEB1A; 226650), Pulkkinen and Uitto (1998) detected compound heterozygosity for premature termination mutations in LAMB3, the recurrent R235X mutation on the maternal allele and a 5-basepair deletion (1438del5; 150310.0010) on the paternal allele. The 1438del5 mutation resulted in a premature termination codon 164 nucleotides downstream from the deletion in exon 14. This report represented the first exception to the general rule that mutations leading to premature termination codons on both alleles result in Herlitz (lethal) JEB, whereas in nonlethal variants at least one allele has a missense or in-frame exon skip mutation.
Floeth and Bruckner-Tuderman (1999) described a family with severe nonlethal junctional EB (JEB1A) who had mutations in both the LAMB3 and type XVII collagen (COL17A1; 113811) genes. The index patient was compound heterozygous for 2 mutations in the COL17A1 gene, L855X (113811.0012) and R1226X (113811.0001), and was heterozygous for the R635X mutation in the LAMB3 gene. As a consequence, 2 functionally related proteins were affected. Absence of collagen XVII and attenuated laminin-5 expression resulted in rudimentary hemidesmosome structure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heterozygotes in this family carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathologic skin phenotype. These observations indicated that the known allelic heterogeneity in junctional EB is further complicated by interactions between unlinked mutations. They also demonstrated that identification of 1 mutation in 1 gene is not sufficient for determination of the genetic basis of junctional EB in a given family.
Intermediate Junctional Epidermolysis Bullosa 1A
In affected members of a family with non-Herlitz type of junctional epidermolysis bullosa (JEB1A; 226650), McGrath et al. (1995) demonstrated compound heterozygosity for mutations in the LAMB3 gene: a 123C-T transition in exon 3, resulting in an arg-to-ter substitution, and a 628G-A transition in the last nucleotide of exon 7, which caused a missense mutation, substituting lysine (AAG) for glutamic acid (GAG) (150310.0006). Immunofluorescence microscopy of the skin basement-membrane zone with monoclonal antibody revealed reduced anti-laminin-5 staining compared with normal controls. The labeling, when examined by immunoelectron microscopy, was present within the lower lamina lucida, immediately below the plane of blister formation. McGrath et al. (1995) did not report the codon residue numbers of the mutations, but the substitutions in this patient were reported by Kivirikko et al. (1996) and Mellerio et al. (1998) to be R42X and E210K.
Severe Junctional Epidermolysis Bullosa 1B
In a study of 14 families with the Herlitz type of junctional EB (JEB1B; 226700), Kivirikko et al. (1996) found that 2 premature termination codon mutations in the LAMB3 gene, R42X and R635X (150310.0001), accounted for over 50% of the mutant LAMB3 alleles. A de novo mutation for R42X was observed in 1 family.
Posteraro et al. (1998) described a patient with a nonlethal variant of junctional epidermolysis bullosa (JEB1A; 226650) who was found to be compound heterozygous for mutations affecting the LAMB3 gene. From his father he had inherited a deletion of a single base (904delT) leading to frameshift and a premature termination codon, which resulted in mRNA decay. From his mother he had inherited a G-to-A transition at the last base of exon 7 (628G-A), resulting in a glu210-to-lys (E210K) substitution (150310.0006). The 628G-A mutation altered the correct splicing of LAMB3 pre-mRNA giving rise to 2 aberrant mRNAs, in addition to the RNA transcripts carrying the G-to-A substitution. The findings were considered compatible with the reduced expression of mutated laminin-5 molecules with altered biologic activity, and the mild junctional EB phenotype observed in the patient. Mavilio et al. (2006) transduced epidermal cells from this patient with a retroviral vector expressing LAMB3 and successfully transplanted 9 genetically corrected cultured epidermal skin grafts onto the anterior upper regions of the patient's legs. Retroviral integration site analysis indicated that the regenerated epidermis was maintained by a defined repertoire of transduced stem cells.
Mellerio et al. (1998) found the glu210-to-lys (E210K) mutation on one allele of the LAMB3 gene in 3 unrelated patients, one of whom had previously been reported by McGrath et al. (1995), with a nonlethal variant of epidermolysis bullosa (JEB1A; 226650); different nonsense mutations were found on the second allele (see, e.g., 150310.0003).
For discussion of the E210K mutation in the LAMB3 gene that was found in compound heterozygous state in a patient with a nonlethal variant of junctional EB by Posteraro et al. (1998), see 150310.0005.
In a 46-year-old man (patient 078-01) with generalized non-Herlitz junctional EB who was compound heterozygous for germline R635X (150310.0001) and E210K mutations in the LAMB3 gene and who had reversion to clinically unaffected skin on his left lower leg, Pasmooij et al. (2007) identified 2 different somatic second-site mutations on the E210K allele in 2 different lower leg biopsies (150310.0012 and 150310.0013, respectively). Reversion of the inherited R635X mutation did not occur. In a 64-year-old man (patient 029-01) who was homozygous for the germline E210K mutation and who had reversion of EB on his upper arms and shoulders, Pasmooij et al. (2007) identified 3 different somatic second-site mutations from 3 different biopsies of the newly normal skin (150310.0014-150310.0016, respectively).
In each of 2 apparently unrelated Japanese families, Takizawa et al. (1998) identified compound heterozygosity for LAMB3 mutations as the basis of Herlitz junctional epidermolysis bullosa (JEB1B; 226700). One of the mutations, gln166 to ter (Q166X) (CAG to TAG), was found in the maternal allele of family 1 and the paternal allele of family 2. Conversely, the other mutation, trp610 to ter (W610X; 150310.0008) (TTG to TGA), was found in the paternal allele of family 1 and the maternal allele of family 2. Haplotype analyses with intragenic LAMB3 polymorphisms suggested that both mutations had arisen independently in these 2 families. Both mutations created a premature translation termination codon predicting truncated beta-3 chains that lead to absent expression of laminin-5 in the epidermal basement membrane zone. Based on these results, DNA-based prenatal diagnosis was performed by chorionic villus sampling for subsequent pregnancies in both families. Both fetuses were found to be heterozygous carriers of the W610X mutation and a normal LAMB3 allele, indicating that they were phenotypically unaffected.
For discussion of the trp610-to-ter (W610X) mutation in the LAMB3 gene that was found in compound heterozygous state in families with Herlitz junctional epidermolysis bullosa (JEB1B; 226700) by Takizawa et al. (1998), see 150310.0007.
Takizawa et al. (1998) described a gln936-to-ter (Q936X) mutation in exon 19 of the LAMB3 gene. The patient in whom the mutation was found was born with extensive blistering and demonstrated negative immunofluorescence staining for laminin-5, and transmission electron microscopy showed tissue separation within the lamina lucida of the dermal-epidermal junction, diagnostic of Herlitz junctional epidermolysis bullosa (JEB1B; 226700). The mother of the proband was found to be a heterozygous carrier for the mutation, whereas the father demonstrated the wildtype LAMB3 allele only. Nonpaternity was excluded by 13 microsatellite markers in 6 different chromosomes. Genotype analysis using 28 microsatellite markers spanning chromosome 1 revealed that the patient had maternal primary heterodisomy as well as meroisodisomy within 2 regions of chromosome 1, one on 1p and the other on 1q, the latter region containing the maternal LAMB3 mutation. These results suggested that the disorder in the patient results from reduction to homozygosity of the maternal LAMB3 mutation on 1q32. Takizawa et al. (1998) indicated that uniparental disomy had been demonstrated for 16 human autosomes, as well as for the X and Y chromosomes (Engel, 1993; Ledbetter and Engel, 1995; Benlian et al., 1996).
In a 27-year-old woman with nonlethal junctional epidermolysis bullosa (JEB1A; 226650) and her identically affected younger brother, Pulkkinen and Uitto (1998) found a 5-bp deletion (1438del5) in the LAMB3 gene that resulted in a premature termination codon 164 nucleotides downstream from the deletion within exon 14. The mutation was present in compound heterozygous state with the frequent R635X (150310.0001) mutation. Pulkkinen and Uitto (1998) could provide no ready explanation for the discrepancy between genotype and expected phenotype in this case. Mosaicism as a result of gene conversion, as demonstrated previously in nonlethal junctional EB due to mutation in the COL17A1 gene (113811) by Jonkman et al. (1997), was unlikely because the affected brother had a similar phenotypic presentation.
In a patient with severe junctional epidermolysis bullosa (JEB1B; 226700) at birth, Gache et al. (2001) found a heterozygous A-to-G deletion at position 1587 of exon 13. This 1587delAG deletion led to a shift of the reading frame and resulted in a downstream premature termination codon in exon 14. This mutation was in compound heterozygous state with the R635X (150310.0001) mutation.
In a 46-year-old man (patient 078-01) with generalized non-Herlitz junctional epidermolysis bullosa (JEB1A; 226650) who was compound heterozygous for germline R635X (150310.0001) and E210K (150310.0006) mutations in the LAMB3 gene and who had reversion to clinically unaffected skin on his left lower leg, Pasmooij et al. (2007) identified 2 different somatic second-site mutations on the E210K allele in 2 different lower leg biopsies. One was a c.628+42G-A transition in intron 7 of the LAMB3 gene which causes the use of a cryptic splice site, and the other was a c.596G-C transversion in exon 7, resulting in a gly199-to-ala substitution (G199A; 150310.0013). The compensatory mutations were not found in fibroblasts taken from the same biopsies or in more than 80 control subjects. Analysis of mRNA from the 2 lower leg biopsy sites showed predominance of the normally spliced 269-bp amplimer in addition to 3 shorter transcripts known to occur with the E210K mutation; at the c.628+42G-A site there was also a 335-bp product. Reversion of the inherited R635X mutation did not occur.
For discussion of the compensatory second-site somatic gly199-to-ala (G199A) mutation in the LAMB3 gene that was found in a patient with generalized non-Herlitz junctional epidermolysis bullosa (JEB1A; 226650) by Pasmooij et al. (2007), see 150310.0012.
In a 64-year-old man (patient 029-01) with generalized non-Herlitz junctional epidermolysis bullosa (JEB1A; 226650) who was homozygous for the E210K germline mutation in LAMB3 (150310.0006) and who had reversion to clinically normal skin at his upper arms, shoulders, and chest, Pasmooij et al. (2007) identified 3 different somatic second-site mutations on 1 of the E210K alleles in 3 different biopsies of reverted skin: a c.565-3C-T transition in the 3-prime splice site of intron 6; a c.619A-C transversion in exon 7, resulting in a lys207-to-gln substitution (K207Q; 150310.0015); and a c.629-1G-A transition in the 3-prime splice site of intron 7 (150310.0016), respectively. The second-site mutations were not found in more than 160 control chromosomes. Analysis of mRNA from the c.565-3C-T and K207Q biopsy sites revealed predominance of the full-length mRNA transcript, with 3 shorter transcripts known to occur with the E210K mutation present as well; at the c.629-1G-A biopsy site there was a predominance of 1 of the shorter transcripts, with a 66-bp deletion.
For discussion of the compensatory second-site somatic lys207-to-gln (K207Q) mutation in the LAMB3 gene that was found in a patient with generalized non-Herlitz junctional epidermolysis bullosa (JEB1A; 226650) by Pasmooij et al. (2007), see 150310.0014.
For discussion of the compensatory second-site somatic splice site mutation in the LAMB3 gene, a c.629-1G-A transition in the 3-prime splice site of intron 7, that was found in a patient with generalized non-Herlitz junctional epidermolysis bullosa (JEB1A; 226650) by Pasmooij et al. (2007), see 150310.0014.
By whole-exome sequencing in a family (Family 1) with hypoplastic amelogenesis imperfecta (AI1A; 104530), Kim et al. (2013) identified a heterozygous 8-bp deletion (NM_000228.2, c.3446_3453delGACTGGAG) in the last exon of the LAMB3 gene, which was predicted to result in a frameshift and premature termination (Gly1149GlufsTer8). The 6.5-year-old proposita had thin, grooved, and pitted enamel in both her primary and secondary dentition. Her mother, whose dentition was within normal limits, reported that the girl's father had dentition similar to that in the proposita, but he was not available for study. The mutation was not found in the 1000 Genomes Project database. This family had previously been reported as family AI-23 by Kim et al. (2006).
By whole-exome sequencing in a family (Family 2) with hypoplastic amelogenesis imperfecta (AI1A; 104530), Kim et al. (2013) identified a heterozygous 1-bp substitution in exon 23 of the LAMB3 gene (NM_000228.2, c.3431C-A), resulting in a ser114-to-ter (S1144X) substitution. The proposita presented with hypoplastic enamel characterized by deep grooves and pits. Her mother and maternal aunt were similarly affected. The mutation segregated with the disorder in the family and was not found in the 1000 Genomes Project database. In addition to the c.3431C-A mutation, all 3 affected individuals carried a c.3432A-G substitution in the LAMB3 gene, which was found in the dbSNP database (rs1049607) and was therefore not thought to be disease causing.
In 6 affected members of an Irish family (AI-17) segregating autosomal dominant hypoplastic amelogenesis imperfecta (AI1A; 104530), Poulter et al. (2014) identified a heterozygous 1-bp insertion in the LAMB3 gene (NM_000228, c.3392_3393insG), resulting in a frameshift and premature termination (Glu1133GlyfsTer27). All affected family members presented with generalized, irregular hypoplastic amelogenesis imperfecta with no other health problems or skin manifestations.
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