Entry - #610915 - OSTEOGENESIS IMPERFECTA, TYPE VIII; OI8 - OMIM
# 610915

OSTEOGENESIS IMPERFECTA, TYPE VIII; OI8


Alternative titles; symbols

OI, TYPE VIII


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
1p34.2 Osteogenesis imperfecta, type VIII 610915 AR 3 P3H1 610339
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Height
- Short stature, disproportionate
- Dwarfism, short-limbed
HEAD & NECK
Head
- Wide open anterior fontanelle
- Soft skull
- Open sutures
Face
- Round face
Eyes
- White sclerae
- Proptosis
Teeth
- No dentinogenesis imperfecta
CHEST
External Features
- Short, barrel-shaped chest
Ribs Sternum Clavicles & Scapulae
- Thin ribs
SKELETAL
- Bone fragility
- Severe osteopenia
- Normal bone age
- Multiple fractures, present at birth
- Joint laxity
Skull
- Poorly ossified skull
- Wormian bones
Spine
- Platyspondyly
- Scoliosis
- Kyphosis
- Vertebral compression fractures
Limbs
- Thin, gracile long bones
- Radial bowing
- Femoral bowing
- Tibial bowing
- Bulbous metaphyses
- Externally rotated/abducted legs
Hands
- Long phalanges
- Short metacarpals
NEUROLOGIC
Central Nervous System
- Delayed development
LABORATORY ABNORMALITIES
- Type 1 collagen overmodification
- Absent-decreased prolyl 3-hydroxylation at collagen I alpha-1 pro986
MOLECULAR BASIS
- Caused by mutation in the leucine- and proline-enriched proteoglycan 1 gene (LEPRE1, 610339.0001)
Osteogenesis imperfecta - PS166200 - 26 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p34.2 Osteogenesis imperfecta, type VIII AR 3 610915 P3H1 610339
3p22.3 Osteogenesis imperfecta, type VII AR 3 610682 CRTAP 605497
5q33.1 Osteogenesis imperfecta, type XVII AR 3 616507 SPARC 182120
6q14.1 Osteogenesis imperfecta, type XVIII AR 3 617952 TENT5A 611357
7p22.1 Osteogenesis imperfecta, type XXI AR 3 619131 KDELR2 609024
7q21.3 Osteogenesis imperfecta, type IV AD 3 166220 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type II AD 3 166210 COL1A2 120160
7q21.3 Osteogenesis imperfecta, type III AD 3 259420 COL1A2 120160
8p21.3 Osteogenesis imperfecta, type XIII AR 3 614856 BMP1 112264
9q31.2 Osteogenesis imperfecta, type XIV AR 3 615066 TMEM38B 611236
11p15.5 Osteogenesis imperfecta, type V AD 3 610967 IFITM5 614757
11p11.2 Osteogenesis imperfecta, type XVI AR 3 616229 CREB3L1 616215
11q13.5 Osteogenesis imperfecta, type X AR 3 613848 SERPINH1 600943
11q23.3 Osteogenesis imperfecta, type XXIII AR 3 620639 PHLDB1 612834
12q13.12 Osteogenesis imperfecta, type XV AR 3 615220 WNT1 164820
12q13.13 Osteogenesis imperfecta, type XII AR 3 613849 SP7 606633
15q22.31 Osteogenesis imperfecta, type IX AR 3 259440 PPIB 123841
15q25.1 Osteogenesis imperfecta, type XX AR 3 618644 MESD 607783
17p13.3 Osteogenesis imperfecta, type VI AR 3 613982 SERPINF1 172860
17q21.2 Osteogenesis imperfecta, type XI AR 3 610968 FKBP10 607063
17q21.33 Osteogenesis imperfecta, type I AD 3 166200 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type III AD 3 259420 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type II AD 3 166210 COL1A1 120150
17q21.33 Osteogenesis imperfecta, type IV AD 3 166220 COL1A1 120150
22q13.2 Osteogenesis imperfecta, type XXII AR 3 619795 CCDC134 618788
Xp22.12 Osteogenesis imperfecta, type XIX XLR 3 301014 MBTPS2 300294

TEXT

A number sign (#) is used with this entry because this form of autosomal recessive osteogenesis imperfecta (OI8) is caused by homozygous or compound heterozygous mutation in the LEPRE1 gene (P3H3; 610339) on chromosome 1p32.


Description

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.


Clinical Features

Cabral et al. (2007) described 5 patients with a lethal/severe osteogenesis imperfecta-like bone dysplasia caused by mutation in the LEPRE1 gene. The phenotype of the probands overlapped Sillence lethal type II/severe type III osteogenesis imperfecta (see 166210 and 259440), with severe osteoporosis, shortened long bones, and a soft skull with wide open fontanel. However, in contrast to the classic blue sclerae, triangular face, and narrow thorax of severe and lethal osteogenesis imperfecta, their probands had white sclerae, a round face, and a short barrel-shaped chest. Prenatal radiographs demonstrated gracile, undermineralized ribs and long bones. Multiple fractures were present at birth. Long bone radiographs of surviving probands showed bulbous metaphyses and apparent matrix disorganization. Their hands appeared relatively long compared to their forearms, with long phalanges, short metacarpals, and disorganized matrix. Vertebral compression fractures occurred in 2 of the surviving probands by 14 months and 5 years of age, respectively. Their bone density was lower than almost all individuals with severe osteogenesis imperfecta. Four probands, including the 3 lethal cases, were African, African American, or Afro-Caribbean. The fifth proband was Pakistani. The parents of proband 1 denied consanguinity and had a previous affected child who died in Africa; the parents of proband 2 had a second affected child.


Molecular Genetics

By linkage studies, Wallis et al. (1993) excluded the COL1A1 and COL1A2 (120160) loci as the site of the mutation in this form of osteogenesis imperfecta; the combined lod scores were -10.6 for COL1A1 and -11.2 for COL1A2. Furthermore, they examined the type I procollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the 8 families studied by linkage plus 1 further family; no evidence for defects in the synthesis, structure, secretion, or posttranslational modification of the chains of type I procollagen was found.

Prolyl 3-hydroxylase 1 (P3H1), the product of the LEPRE1 gene, hydroxylates a single proline, pro986 of the collagen type I alpha-1 chain (COL1A1; 120150) and forms a complex with cartilage-associated protein (CRTAP; 605497) and cyclophilin B (123841). Because the enzymatic activity in the 3-hydroxylation complex resides in P3H1, Cabral et al. (2007) postulated that its absence would result in severe bone dysplasia. They screened individuals with lethal/severe osteogenesis imperfecta-like bone dysplasia and overmodified collagen but without a type I collagen mutation detected by complete cDNA sequencing of both collagen chains. Real-time RT-PCR of total fibroblast RNA identified 5 individuals, 3 with lethal and 2 with severe bone dysplasia, whose LEPRE1 mRNA was 5 to 21% that of normal controls. All 5 individuals carried LEPRE1 mutations on both alleles (610339.0001-610339.0004). A common mutant allele was found in the African and African American probands (610339.0001).

Willaert et al. (2009) screened the LEPRE1, CRTAP, and PPIB (123841) genes in 20 severe/lethal OI patients who were negative for mutation in type I collagen genes, and identified 4 homozygous and compound heterozygous mutations in the LEPRE1 gene in 4 probands, respectively (610339.0005-610339.0007). No mutations were found in CRTAP or PPIB. Two of the patients were relatively long-lived (alive at 17 years and 8 years of age, respectively). The authors noted that although at birth, clinical and radiologic features of these patients were virtually indistinguishable from those of patients with autosomal dominant severe/lethal OI, follow-up evaluation revealed the development of a severe osteochondrodysplasia with distinctive features, including complete disappearance of the honeycomb-type trabecular agglomeration, extreme osteoporosis, and additional widening of the rhizomelic diaphyses, accompanied by progressive narrowing and bowing of the mesomelic diaphysis, with reduction of the knee joint spaces to a mere line between the femora and tibiae.


Population Genetics

To determined the carrier frequency of the LEPRE1 (1080+1G-T) mutation, Cabral et al. (2012) screened genomic DNA African American and African cohorts. Among 3,055 African Americans from the Mid-Atlantic United States tested, 12 carriers were identified for a frequency of 0.39% (1 in 255). Among Ghanaians, 9 carriers were found among 453 individuals for a frequency of 1.99% (1 in 50). Among Nigerians, 10 of 818 were carriers (1.22%, 1 in 182). Among total West Africans, 19 of 1,284 were carriers (1.48%, 1 in 68). The mutation was not detected in Africa outside of West Africa. Among 12 unrelated West African families with 16 independent mutant alleles, Cabral et al. (2012) identified a conserved haplotype surrounding the LEPRE1 gene extending from between D1S2861 to the region between markers STR3 and STR5. Using linkage disequilibrium analysis, Cabral et al. (2012) estimated the mutation to have originated 650 and 900 years before the present (1100 to 1350 CE).


Nomenclature

Cabral et al. (2007) suggested that defects in LEPRE1 resulting in a lethal to severe recessive bone dysplasia that is characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses should be classified as type VIII osteogenesis imperfecta.


REFERENCES

  1. Cabral, W. A., Barnes, A. M., Adeyemo A., Cushing, K., Chitayat, D., Porter, F. D., Panny, S. R., Gulamali-Majid, F., Tishkoff, S. A., Rebbeck, T. R., Gueye, S. M., Bailey-Wilson, J. E., Brody, L. C., Rotimi, C. N., Marini, J. C. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet. Med. 14: 543-551, 2012. [PubMed: 22281939, related citations] [Full Text]

  2. Cabral, W. A., Chang, W., Barnes, A. M., Weis, M., Scott, M. A., Leikin, S., Makareeva, E., Kuznetsova, N. V., Rosenbaum, K. N., Tifft, C. J., Bulas, D. I., Kozma, C., Smith, P. A., Eyre, D. R., Marini, J. C. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nature Genet. 39: 359-365, 2007. Note: Erratum: Nature Genet. 40: 927 only, 2008. [PubMed: 17277775, related citations] [Full Text]

  3. Sillence, D. O., Senn, A., Danks, D. M. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979. [PubMed: 458828, related citations] [Full Text]

  4. Viljoen, D., Beighton, P. Osteogenesis imperfecta type III: an ancient mutation in Africa?. Am. J. Med. Genet. 27: 907-912, 1987. [PubMed: 3425600, related citations] [Full Text]

  5. Wallis, G. A., Sykes, B., Byers, P. H., Mathew, C. G., Viljoen, D., Beighton, P. Osteogenesis imperfecta type III: mutations in the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily responsible. J. Med. Genet. 30: 492-496, 1993. [PubMed: 8100856, related citations] [Full Text]

  6. Willaert, A., Malfait, F., Symoens, S., Gevaert, K., Kayserili, H., Megarbane, A., Mortier, G., Leroy, J. G., Coucke, P. J., De Paepe, A. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J. Med. Genet. 46: 233-241, 2009. [PubMed: 19088120, related citations] [Full Text]


Ada Hamosh - updated : 9/28/2012
Marla J. F. O'Neill - updated : 10/15/2009
Creation Date:
Victor A. McKusick : 4/5/2007
carol : 01/14/2015
carol : 5/2/2013
alopez : 10/2/2012
alopez : 10/2/2012
alopez : 10/2/2012
terry : 9/28/2012
wwang : 10/29/2009
terry : 10/15/2009
alopez : 7/14/2008
alopez : 4/5/2007
alopez : 4/5/2007
alopez : 4/5/2007

# 610915

OSTEOGENESIS IMPERFECTA, TYPE VIII; OI8


Alternative titles; symbols

OI, TYPE VIII


ORPHA: 216804, 216812, 666;   DO: 0110336;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
1p34.2 Osteogenesis imperfecta, type VIII 610915 Autosomal recessive 3 P3H1 610339

TEXT

A number sign (#) is used with this entry because this form of autosomal recessive osteogenesis imperfecta (OI8) is caused by homozygous or compound heterozygous mutation in the LEPRE1 gene (P3H3; 610339) on chromosome 1p32.


Description

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.


Clinical Features

Cabral et al. (2007) described 5 patients with a lethal/severe osteogenesis imperfecta-like bone dysplasia caused by mutation in the LEPRE1 gene. The phenotype of the probands overlapped Sillence lethal type II/severe type III osteogenesis imperfecta (see 166210 and 259440), with severe osteoporosis, shortened long bones, and a soft skull with wide open fontanel. However, in contrast to the classic blue sclerae, triangular face, and narrow thorax of severe and lethal osteogenesis imperfecta, their probands had white sclerae, a round face, and a short barrel-shaped chest. Prenatal radiographs demonstrated gracile, undermineralized ribs and long bones. Multiple fractures were present at birth. Long bone radiographs of surviving probands showed bulbous metaphyses and apparent matrix disorganization. Their hands appeared relatively long compared to their forearms, with long phalanges, short metacarpals, and disorganized matrix. Vertebral compression fractures occurred in 2 of the surviving probands by 14 months and 5 years of age, respectively. Their bone density was lower than almost all individuals with severe osteogenesis imperfecta. Four probands, including the 3 lethal cases, were African, African American, or Afro-Caribbean. The fifth proband was Pakistani. The parents of proband 1 denied consanguinity and had a previous affected child who died in Africa; the parents of proband 2 had a second affected child.


Molecular Genetics

By linkage studies, Wallis et al. (1993) excluded the COL1A1 and COL1A2 (120160) loci as the site of the mutation in this form of osteogenesis imperfecta; the combined lod scores were -10.6 for COL1A1 and -11.2 for COL1A2. Furthermore, they examined the type I procollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the 8 families studied by linkage plus 1 further family; no evidence for defects in the synthesis, structure, secretion, or posttranslational modification of the chains of type I procollagen was found.

Prolyl 3-hydroxylase 1 (P3H1), the product of the LEPRE1 gene, hydroxylates a single proline, pro986 of the collagen type I alpha-1 chain (COL1A1; 120150) and forms a complex with cartilage-associated protein (CRTAP; 605497) and cyclophilin B (123841). Because the enzymatic activity in the 3-hydroxylation complex resides in P3H1, Cabral et al. (2007) postulated that its absence would result in severe bone dysplasia. They screened individuals with lethal/severe osteogenesis imperfecta-like bone dysplasia and overmodified collagen but without a type I collagen mutation detected by complete cDNA sequencing of both collagen chains. Real-time RT-PCR of total fibroblast RNA identified 5 individuals, 3 with lethal and 2 with severe bone dysplasia, whose LEPRE1 mRNA was 5 to 21% that of normal controls. All 5 individuals carried LEPRE1 mutations on both alleles (610339.0001-610339.0004). A common mutant allele was found in the African and African American probands (610339.0001).

Willaert et al. (2009) screened the LEPRE1, CRTAP, and PPIB (123841) genes in 20 severe/lethal OI patients who were negative for mutation in type I collagen genes, and identified 4 homozygous and compound heterozygous mutations in the LEPRE1 gene in 4 probands, respectively (610339.0005-610339.0007). No mutations were found in CRTAP or PPIB. Two of the patients were relatively long-lived (alive at 17 years and 8 years of age, respectively). The authors noted that although at birth, clinical and radiologic features of these patients were virtually indistinguishable from those of patients with autosomal dominant severe/lethal OI, follow-up evaluation revealed the development of a severe osteochondrodysplasia with distinctive features, including complete disappearance of the honeycomb-type trabecular agglomeration, extreme osteoporosis, and additional widening of the rhizomelic diaphyses, accompanied by progressive narrowing and bowing of the mesomelic diaphysis, with reduction of the knee joint spaces to a mere line between the femora and tibiae.


Population Genetics

To determined the carrier frequency of the LEPRE1 (1080+1G-T) mutation, Cabral et al. (2012) screened genomic DNA African American and African cohorts. Among 3,055 African Americans from the Mid-Atlantic United States tested, 12 carriers were identified for a frequency of 0.39% (1 in 255). Among Ghanaians, 9 carriers were found among 453 individuals for a frequency of 1.99% (1 in 50). Among Nigerians, 10 of 818 were carriers (1.22%, 1 in 182). Among total West Africans, 19 of 1,284 were carriers (1.48%, 1 in 68). The mutation was not detected in Africa outside of West Africa. Among 12 unrelated West African families with 16 independent mutant alleles, Cabral et al. (2012) identified a conserved haplotype surrounding the LEPRE1 gene extending from between D1S2861 to the region between markers STR3 and STR5. Using linkage disequilibrium analysis, Cabral et al. (2012) estimated the mutation to have originated 650 and 900 years before the present (1100 to 1350 CE).


Nomenclature

Cabral et al. (2007) suggested that defects in LEPRE1 resulting in a lethal to severe recessive bone dysplasia that is characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses should be classified as type VIII osteogenesis imperfecta.


See Also:

Viljoen and Beighton (1987)

REFERENCES

  1. Cabral, W. A., Barnes, A. M., Adeyemo A., Cushing, K., Chitayat, D., Porter, F. D., Panny, S. R., Gulamali-Majid, F., Tishkoff, S. A., Rebbeck, T. R., Gueye, S. M., Bailey-Wilson, J. E., Brody, L. C., Rotimi, C. N., Marini, J. C. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet. Med. 14: 543-551, 2012. [PubMed: 22281939] [Full Text: https://doi.org/10.1038/gim.2011.44]

  2. Cabral, W. A., Chang, W., Barnes, A. M., Weis, M., Scott, M. A., Leikin, S., Makareeva, E., Kuznetsova, N. V., Rosenbaum, K. N., Tifft, C. J., Bulas, D. I., Kozma, C., Smith, P. A., Eyre, D. R., Marini, J. C. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nature Genet. 39: 359-365, 2007. Note: Erratum: Nature Genet. 40: 927 only, 2008. [PubMed: 17277775] [Full Text: https://doi.org/10.1038/ng1968]

  3. Sillence, D. O., Senn, A., Danks, D. M. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979. [PubMed: 458828] [Full Text: https://doi.org/10.1136/jmg.16.2.101]

  4. Viljoen, D., Beighton, P. Osteogenesis imperfecta type III: an ancient mutation in Africa?. Am. J. Med. Genet. 27: 907-912, 1987. [PubMed: 3425600] [Full Text: https://doi.org/10.1002/ajmg.1320270417]

  5. Wallis, G. A., Sykes, B., Byers, P. H., Mathew, C. G., Viljoen, D., Beighton, P. Osteogenesis imperfecta type III: mutations in the type I collagen structural genes, COL1A1 and COL1A2, are not necessarily responsible. J. Med. Genet. 30: 492-496, 1993. [PubMed: 8100856] [Full Text: https://doi.org/10.1136/jmg.30.6.492]

  6. Willaert, A., Malfait, F., Symoens, S., Gevaert, K., Kayserili, H., Megarbane, A., Mortier, G., Leroy, J. G., Coucke, P. J., De Paepe, A. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J. Med. Genet. 46: 233-241, 2009. [PubMed: 19088120] [Full Text: https://doi.org/10.1136/jmg.2008.062729]


Contributors:
Ada Hamosh - updated : 9/28/2012
Marla J. F. O'Neill - updated : 10/15/2009

Creation Date:
Victor A. McKusick : 4/5/2007

Edit History:
carol : 01/14/2015
carol : 5/2/2013
alopez : 10/2/2012
alopez : 10/2/2012
alopez : 10/2/2012
terry : 9/28/2012
wwang : 10/29/2009
terry : 10/15/2009
alopez : 7/14/2008
alopez : 4/5/2007
alopez : 4/5/2007
alopez : 4/5/2007