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1.
PLoS Genet ; 12(7): e1006156, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27441836

RESUMEN

Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.


Asunto(s)
Calcio/metabolismo , Colágeno Tipo I/biosíntesis , Canales Iónicos/genética , Osteogénesis Imperfecta/genética , Adulto , Señalización del Calcio , Colágeno Tipo I/metabolismo , Consanguinidad , Análisis Mutacional de ADN , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Femenino , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Lactante , Masculino , Linaje , Procesamiento Proteico-Postraduccional
2.
Am J Hum Genet ; 87(5): 708-12, 2010 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-21035103

RESUMEN

Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.


Asunto(s)
Colágeno Tipo XI/genética , Mutación , Osteocondrodisplasias/genética , Cartílago/patología , Pérdida Auditiva/genética , Humanos , Osteocondrodisplasias/patología
3.
Genet Med ; 14(9): 811-8, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22653535

RESUMEN

PURPOSE: The aim of this study was to characterize the clinical phenotype of patients with tetrasomy of the distal 15q chromosome in the form of a neocentric marker chromosome and to evaluate whether the phenotype represents a new clinical syndrome or is a phenocopy of Shprintzen-Goldberg syndrome. METHODS: We carried out comprehensive clinical evaluation of four patients who were identified with a supernumerary marker chromosome. The marker chromosome was characterized by G-banding, fluorescence in situ hybridization, single nucleotide polymorphism oligonucleotide microarray analysis, and immunofluorescence with antibodies to centromere protein C. RESULTS: The marker chromosomes were categorized as being neocentric with all showing tetrasomy for regions distal to 15q25 and the common region of overlap being 15q26→qter. CONCLUSION: Tetrasomy of 15q26 likely results in a distinct syndrome as the patients with tetrasomy 15q26 share a strikingly more consistent phenotype than do the patients with Shprintzen-Goldberg syndrome, who show remarkable clinical variation.


Asunto(s)
Aracnodactilia/diagnóstico , Cromosomas Humanos Par 15 , Craneosinostosis/diagnóstico , Síndrome de Marfan/diagnóstico , Tetrasomía/genética , Adulto , Aracnodactilia/genética , Aracnodactilia/patología , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Bandeo Cromosómico , Craneosinostosis/genética , Craneosinostosis/patología , Femenino , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Fenotipo , Síndrome , Tetrasomía/patología
4.
BMC Med Genet ; 13: 26, 2012 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-22487062

RESUMEN

BACKGROUND: Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here. METHODS: LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b). RESULTS: Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002). CONCLUSIONS: Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.


Asunto(s)
Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Osteoporosis/genética , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Animales , Densidad Ósea/genética , Células CHO , Cricetinae , Cricetulus , Genes Reporteros , Heterocigoto , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Mutación Missense , Osteogénesis Imperfecta/genética , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Transfección , Triptófano Hidroxilasa/metabolismo
5.
Am J Med Genet A ; 158A(7): 1574-8, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22639450

RESUMEN

We report on maternal half-sibs born to unaffected, non-consanguineous parents with classical Shprintzen-Goldberg syndrome (SGS) who had in addition intestinal malrotation and an aberrant subclavian artery. In one other SGS family germline mosaicism has been described. SGS is molecularly heterogeneous and has been linked to mutations in three genomic loci. This suggests there may be multiple other genetic factors that result in a common clinical phenotype and a number of investigators have implicated a fourth region (15q25-qter) in the etiology of SGS.


Asunto(s)
Aracnodactilia/genética , Craneosinostosis/genética , Mutación de Línea Germinal , Síndrome de Marfan/genética , Mosaicismo , Facies , Femenino , Fibrilinas , Humanos , Lactante , Masculino , Proteínas de Microfilamentos/genética , Fenotipo
6.
Am J Med Genet A ; 158A(2): 309-14, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22246659

RESUMEN

Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proα1(XI) chain of type XI collagen, COL11A1. The first of two cases reported here was the affected offspring of first cousins and sequence analysis excluded mutations in COL11A1. Consequently, whole-genome SNP genotyping was performed to identify blocks of homozygosity, identical-by-descent, wherein the disease locus would reside. COL11A1 was not within a region of homozygosity, further excluding it as the disease locus, but the gene encoding the proα2(XI) chain of type XI collagen, COL11A2, was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. Exon trapping demonstrated that the mutation resulted in skipping of exon 18 and predicted deletion of 18 amino acids from the triple helical domain of the protein. In the second case, heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. These findings thus demonstrate that fibrochondrogenesis can result from either recessively or dominantly inherited mutations in COL11A2.


Asunto(s)
Colágeno Tipo XI/genética , Enanismo/genética , Enanismo/patología , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Sitios de Empalme de ARN/genética , Enanismo/diagnóstico , Exones , Genes Dominantes , Genes Recesivos , Genotipo , Humanos , Recién Nacido , Intrones , Osteocondrodisplasias/diagnóstico , Polimorfismo de Nucleótido Simple , Eliminación de Secuencia
7.
BMC Med Genet ; 12: 153, 2011 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-22107760

RESUMEN

BACKGROUND: Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD. METHODS: We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging. RESULTS: Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89). CONCLUSION: Our results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad/genética , Interleucina-6/genética , Degeneración del Disco Intervertebral/epidemiología , Degeneración del Disco Intervertebral/genética , Proteínas/genética , Pirofosfatasas/genética , Adolescente , Estudios de Cohortes , Finlandia/epidemiología , Estudios de Asociación Genética , Genotipo , Haplotipos/genética , Humanos , Patrón de Herencia , Degeneración del Disco Intervertebral/patología , Modelos Logísticos , Imagen por Resonancia Magnética , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética , Adulto Joven
8.
Am J Med Genet A ; 155A(7): 1668-72, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21671392

RESUMEN

Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss-of-function mutation in COL9A2, c.843_c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss-of-function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX α chains, α1, α2, and α3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss-of-function mutations in COL9A2 and COL9A3 were found to co-segregate with the loci. Together the data from the present study and the previous studies suggest that loss-of-function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome.


Asunto(s)
Artritis/genética , Colágeno Tipo IX/genética , Enfermedades del Tejido Conjuntivo/genética , Genes Recesivos/genética , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Desprendimiento de Retina/genética , Adulto , Artritis/patología , Secuencia de Bases , Niño , Preescolar , Enfermedades del Tejido Conjuntivo/patología , Femenino , Genotipo , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Masculino , Linaje , Fenotipo , Desprendimiento de Retina/patología
9.
BMC Genet ; 11: 95, 2010 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-20961463

RESUMEN

BACKGROUND: Stress fractures are a significant problem among athletes and soldiers and may result in devastating complications or even permanent handicap. Genetic factors may increase the risk, but no major susceptibility genes have been identified. The purpose of this study was to search for possible genetic factors predisposing military conscripts to femoral neck stress fractures. RESULTS: Eight genes involved in bone metabolism or pathology (COL1A1, COL1A2, OPG, ESR1, VDR, CTR, LRP5, IL-6) were examined in 72 military conscripts with a femoral neck stress fracture and 120 controls. The risk of femoral neck stress fracture was significantly higher in subjects with low weight and body mass index (BMI). An interaction between the CTR (rs1801197) minor allele C and the VDR C-A haplotype was observed, and subjects lacking the C allele in CTR and/or the C-A haplotype in VDR had a 3-fold higher risk of stress fracture than subjects carrying both (OR = 3.22, 95% CI 1.38-7.49, p = 0.007). In addition, the LRP5 haplotype A-G-G-C alone and in combination with the VDR haplotype C-A was associated with stress fractures through reduced body weight and BMI. CONCLUSIONS: Our findings suggest that genetic factors play a role in the development of stress fractures in individuals subjected to heavy exercise and mechanical loading. The present results can be applied to the design of future studies that will further elucidate the genetics of stress fractures.


Asunto(s)
Fracturas del Cuello Femoral/genética , Fracturas por Estrés/genética , Predisposición Genética a la Enfermedad , Personal Militar , Adulto , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Adulto Joven
10.
Am J Med Genet A ; 152A(10): 2437-43, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20734336

RESUMEN

Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut, and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.


Asunto(s)
Actinas/genética , Aneurisma de la Aorta/genética , Trastornos Cerebrovasculares/genética , Músculo Liso/patología , Mutación Missense , Enfermedades Vasculares/genética , Adolescente , Disección Aórtica/genética , Disección Aórtica/cirugía , Animales , Aorta/patología , Aneurisma de la Aorta/patología , Aneurisma de la Aorta/cirugía , Trastornos Cerebrovasculares/patología , Niño , Femenino , Humanos , Masculino , Ratones , Músculo Liso Vascular/patología , Mutación , Enfermedades Vasculares/cirugía
11.
J Biomed Biotechnol ; 2010: 376927, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20625483

RESUMEN

Collagen V, a fibrillar collagen with important functions in tissues, assembles into distinct chain associations. The most abundant and ubiquitous molecular form is the heterotrimer [alpha1(V)](2)alpha2(V). In the attempt to produce high levels of recombinant collagen V heterotrimer for biomedical device uses, and to identify key factors that drive heterotrimeric chain association, several cell expression systems (yeast, insect, and mammalian cells) have been assayed by cotransfecting the human proalpha1(V) and proalpha2(V) chain cDNAs. Suprisingly, in all recombinant expression systems, the formation of [alpha1(V)](3) homotrimers was considerably favored over the heterotrimer. In addition, pepsin-sensitive proalpha2(V) chains were found in HEK-293 cell media indicating that these cells lack quality control proteins preventing collagen monomer secretion. Additional transfection with Hsp47 cDNA, encoding the collagen-specific chaperone Hsp47, did not increase heterotrimer production. Double immunofluorescence with antibodies against collagen V alpha-chains showed that, contrary to fibroblasts, collagen V alpha-chains did not colocalized intracellularly in transfected cells. Monensin treatment had no effect on the heterotrimer production. The heterotrimer production seems to require specific machinery proteins, which are not endogenously expressed in the expression systems. The different constructs and transfected cells we have generated represent useful tools to further investigate the mechanisms of collagen trimer assembly.


Asunto(s)
Colágeno Tipo V/biosíntesis , Multimerización de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Animales , Línea Celular , Células Clonales , Colágeno Tipo V/química , Técnica del Anticuerpo Fluorescente , Proteínas del Choque Térmico HSP47/metabolismo , Humanos , Insectos/citología , Pichia/metabolismo
12.
Biochem J ; 409(2): 545-54, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-17880280

RESUMEN

Collagen IX is a heterotrimer of three alpha-chains, which consists of three COL domains (collagenous domains) (COL1-COL3) and four NC domains (non-collagenous domains) (NC1-NC4), numbered from the C-terminus. Although collagen IX chains have been shown to associate via their C-terminal NC1 domains and form a triple helix starting from the COL1 domain, it is not known whether chain association can occur at other sites and whether other collagenous and non-collagenous regions are involved. To address this question, we prepared five constructs, two long variants (beginning at the NC4 domain) and three short variants (beginning at the COL2 domain), all ending at the NC2 domain (or NC2 replaced by NC1), to study association and selection of collagen IX alpha-chains. Both long variants were able to associate with NC1 or NC2 at the C-terminus and form various disulfide-bonded trimers, but the specificity of chain selection was diminished compared with full-length chains. Trimers of the long variant ending at NC2 were shown to be triple helical by CD. Short variants were not able to assemble into disulfide-bonded trimers even in the presence of both conserved cysteine residues from the COL1-NC1 junction. Our results demonstrate that collagen IX alpha-chains can associate in the absence of COL1 and NC1 domains to form a triple helix, but the COL2-NC2 region alone is not sufficient for trimerization. The results suggest that folding of collagen IX is a co-operative process involving multiple COL and NC domains and that the COL1-NC1 region is important for chain specificity.


Asunto(s)
Colágeno Tipo IX/química , Colágeno Tipo IX/metabolismo , Secuencia de Aminoácidos , Dicroismo Circular , Datos de Secuencia Molecular , Pliegue de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo
13.
Mol Genet Genomic Med ; 7(8): e802, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31268248

RESUMEN

BACKGROUND: MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. METHODS: Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. RESULTS: The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. CONCLUSIONS: Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Síndrome de Hajdu-Cheney/genética , Metaloproteinasa 2 de la Matriz/genética , Mutación , Secuencia de Bases , Huesos/patología , Niño , Preescolar , ADN/análisis , Análisis Mutacional de ADN , Estudios de Asociación Genética , Genotipo , Síndrome de Hajdu-Cheney/patología , Síndrome de Hajdu-Cheney/fisiopatología , Homocigoto , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Anomalías Musculoesqueléticas , Osteólisis , Fenotipo , Piel/patología , Líquido Sinovial
14.
Hum Mutat ; 29(1): 83-90, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17721977

RESUMEN

Stickler syndrome type I (STL1) is a phenotypically heterogeneous disorder characterized by ocular and extraocular features. It is caused by null-allele mutations in the COL2A1 gene that codes for procollagen II. COL2A1 precursor mRNA undergoes alternative splicing, resulting in two isoforms, a long form including exon 2 (type IIA isoform) and a short form excluding exon 2 (type IIB isoform). The short form is predominantly expressed by differentiated chondrocytes in adult cartilage, and the long form in chondroprogenitor cells during early development and in the vitreous of the eye, which is the only adult tissue containing procollagen IIA. Recent evidence indicates that due to the tissue-specific expression of these two isoforms, premature termination codon mutations in exon 2 cause Stickler syndrome with minimal or no extraocular manifestations. We describe here two mutations in exon 2 of COL2A1 in three patients with predominantly ocular Stickler syndrome: Cys64Stop in two patients, and a novel structural mutation, Cys57Tyr, in one patient. RT-PCR of total lymphoblast RNA from one patient with the Cys64Stop mutation revealed that only the normal allele of the IIA form was present, indicating that the mutation resulted either in complete loss of the allele by nonsense-mediated mRNA decay or by skipping of exon 2 via nonsense-mediated altered splicing, resulting in production of the type IIB isoform. The results of COL2A1 minigene expression studies suggest that both Cys64Stop and Cys57Tyr alter positive cis regulatory elements for splicing, resulting in a lower IIA:IIB ratio.


Asunto(s)
Empalme Alternativo/genética , Codón sin Sentido , Colágeno Tipo II/genética , Enfermedades del Tejido Conjuntivo/genética , Exones , Enfermedades Hereditarias del Ojo/genética , Mutación Missense , Adulto , Secuencia de Bases , Niño , Colágeno Tipo II/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Síndrome
15.
J Clin Invest ; 115(5): 1250-7, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15864348

RESUMEN

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.


Asunto(s)
Huesos/fisiopatología , Colágeno Tipo I/metabolismo , Hiperostosis Cortical Congénita/fisiopatología , Mapeo Cromosómico , Cromosomas Humanos Par 17 , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Dermis/patología , Dermis/ultraestructura , Femenino , Peroné/diagnóstico por imagen , Haplotipos , Humanos , Hiperostosis Cortical Congénita/genética , Lactante , Masculino , Mutación , Linaje , Radiografía , Tibia/diagnóstico por imagen
16.
Mol Cell Biol ; 25(23): 10465-78, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16287859

RESUMEN

The matrilins are a family of four noncollagenous oligomeric extracellular matrix proteins with a modular structure. Matrilins can act as adapters which bridge different macromolecular networks. We therefore investigated the effect of collagen IX deficiency on matrilin-3 integration into cartilage tissues. Mice harboring a deleted Col9a1 gene lack synthesis of a functional protein and produce cartilage fibrils completely devoid of collagen IX. Newborn collagen IX knockout mice exhibited significantly decreased matrilin-3 and cartilage oligomeric matrix protein (COMP) signals, particularly in the cartilage primordium of vertebral bodies and ribs. In the absence of collagen IX, a substantial amount of matrilin-3 is released into the medium of cultured chondrocytes instead of being integrated into the cell layer as in wild-type and COMP-deficient cells. Gene expression of matrilin-3 is not affected in the absence of collagen IX, but protein extraction from cartilage is greatly facilitated. Matrilin-3 interacts with collagen IX-containing cartilage fibrils, while fibrils from collagen IX knockout mice lack matrilin-3, and COMP-deficient fibrils exhibit an intermediate integration. In summary, the integration of matrilin-3 into cartilage fibrils occurs both by a direct interaction with collagen IX and indirectly with COMP serving as an adapter. Matrilin-3 can be considered as an interface component, capable of interconnecting macromolecular networks and mediating interactions between cartilage fibrils and the extrafibrillar matrix.


Asunto(s)
Colágeno Tipo IX/deficiencia , Colágeno Tipo IX/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Animales , Animales Recién Nacidos , Especificidad de Anticuerpos , Células Cultivadas , Condrocitos/metabolismo , Colágeno Tipo IX/química , Colágeno Tipo IX/ultraestructura , Matriz Extracelular/genética , Matriz Extracelular/ultraestructura , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/ultraestructura , Expresión Génica , Glicoproteínas/genética , Sueros Inmunes/inmunología , Inmunohistoquímica , Proteínas Matrilinas , Ratones , Ratones Noqueados , Microscopía Electrónica , Unión Proteica , Solubilidad
17.
PLoS One ; 13(8): e0203313, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30157244

RESUMEN

INTRODUCTION: Osteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. The heritability of OA has been estimated to be 60% for hip OA and 39% for knee OA. Genetic factors behind OA are still largely unknown. Studying families with strong history of OA, facilitates examining the co-segregation of genetic variation and OA. The aim of this study was to identify new, rare genetic factors and novel candidate genes for OA. METHODS: Eight patients from three Finnish families with hip and knee OA were studied using whole exome sequencing. We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions. Expression of identified candidate genes were studied in bone and cartilage tissues and the observed variants were investigated using bioinformatic analyses. RESULTS: Two rare variants co-segregated with OA in two families. In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the OLIG3 gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis. The Arg210Gly variant was estimated to be pathogenic by Polyphen-2 and Mutation taster and the locus is conserved among mammals. In Family 12 the observed variant (c.-127G>T) was located in the transcription start site of the FIP1L1 gene. FIP1L1 participates in the regulation of polyadenylation. The c.-127G>T is located in the transcription start site and may alter the DNA-binding of transcription factors. Both, OLIG3 and FIP1L1 were observed in human bone and cartilage. CONCLUSION: The identified variants revealed novel candidate genes for OA. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to OA.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Predisposición Genética a la Enfermedad , Variación Genética , Osteoartritis de la Cadera/genética , Osteoartritis de la Rodilla/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Huesos/metabolismo , Cartílago/metabolismo , Biología Computacional , Familia , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/metabolismo , Osteoartritis de la Rodilla/metabolismo , ARN Mensajero/metabolismo , Alineación de Secuencia , Secuenciación del Exoma , Factores de Escisión y Poliadenilación de ARNm/metabolismo
18.
J Bone Miner Res ; 22(5): 701-7, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17266399

RESUMEN

UNLABELLED: In the first linkage study on LDD, a common musculoskeletal disorder, a genome-wide scan was performed on 14 Finnish families. The analysis resulted in identification of a putative susceptibility locus for the disease on chromosome 21. INTRODUCTION: Lumbar disc disease (LDD) is a common musculoskeletal disorder that affects approximately 5% of the adult population. Several predisposing genetic and environmental risk factors have been identified for symptomatic LDD (i.e., symptomatic disc herniation and/or sciatic pain), but thus far, no common cause has been identified. MATERIALS AND METHODS: Medical history data were collected from 186 members of 14 Finnish families with LDD. RESULTS: A genome-wide scan resulted in 10 chromosomal regions providing LOD scores >1, and in fine mapping, maximum two-point LOD scores of 2.71, 2.36, and 2.04 were obtained for chromosomes 21 (D21S1257), 4 (D4S399), and 6 (D6S294), respectively. A second fine mapping confirmed the susceptibility of chromosome 21 with a two-point LOD score of 2.06 (D21S1922). In addition, a significant association between LDD and SNP rs716195 was observed (p<0.001), and case-control analysis revealed pointwise significant differences with several markers. Interestingly, the locus for another spinal disorder, ossification of the posterior longitudinal ligament (OPLL), has been mapped to chromosome 21q, partially overlapping with our candidate region. Two candidate genes with aggrecanase activity, ADAMTS-1 and ADAMTS-5, were analyzed in the region, suggesting linkage, leading to the identification of 13 sequence variations. None of the variations were disease-causing, however, because they were observed equally in affected and healthy individuals. CONCLUSIONS: We report here on the first putative susceptibility locus for LDD in the Finnish population. The candidate region on chromosome 21q spans >5.5 cM and contains several interesting genes for further analysis.


Asunto(s)
Cromosomas Humanos Par 21/genética , Predisposición Genética a la Enfermedad/genética , Disco Intervertebral , Vértebras Lumbares , Sitios de Carácter Cuantitativo , Enfermedades de la Columna Vertebral/genética , Proteínas ADAM/genética , Proteína ADAMTS1 , Proteína ADAMTS5 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Mapeo Cromosómico , Femenino , Finlandia , Humanos , Desequilibrio de Ligamiento , Escala de Lod , Masculino , Persona de Mediana Edad
19.
Hum Mutat ; 28(4): 336-44, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17117407

RESUMEN

The importance of the genetic component in high myopia has been well established in population and family studies, but only a few candidate genes have been explored to date. The extracellular matrix small leucine-rich repeat proteins/proteoglycans (SLRPs) regulate collagen fibril diameter and spacing. Given their role in extracellular matrix assembly and expression in the eye, they are likely to regulate its shape and size. Analysis of 85 English and 40 Finnish subjects with high myopia (refractive error of -6 diopters [D] or greater) resulted in 23 sequence variations in four SLRP genes, LUM, FMOD, PRELP, and OPTC. We observed higher number of variations in OPTC in English patients than in controls (p=0.042), and a possibly protective variation in LUM (c.893-105G>A) with p-value of 0.0043. Two intronic variations, six nonsynonymous and one synonymous amino acid changes, were not found in any of the nonmyopic controls. Five changes were detected in opticin, Thr177Arg, Arg229His, Arg325Trp, Gly329Ser, and Arg330His, and all but one (Arg229His) were shown to cosegregate with high myopia in families with incomplete penetrance. A homology model for opticin revealed that Arg229His and Arg325Trp are likely to disrupt the protein structure, and PolyPhen analysis suggested that Thr177Arg, Arg325Trp, and Gly329Ser changes may be damaging. A Leu199Pro change in lumican and Gly147Asp and Arg324Thr variations in fibromodulin are located in the highly conserved leucine-rich repeat (LRR) domains. This study provides new insight into the genetics of high myopia, suggesting that sequence variations in the SLRP genes expressed in the eye may be among the genetic risk factors underlying the pathogenesis of high myopia.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Miopía/genética , Proteoglicanos/genética , Secuencia de Aminoácidos , Proteoglicanos Tipo Condroitín Sulfato/genética , Secuencia Conservada , Análisis Mutacional de ADN , Femenino , Fibromodulina , Humanos , Sulfato de Queratano/genética , Leucina/genética , Lumican , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Alineación de Secuencia
20.
FEBS Lett ; 581(13): 2434-40, 2007 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-17485091

RESUMEN

AlphaI domain integrins have been found in the ascidian Ciona intestinalis. We produced Ciona alpha1I domain as a recombinant protein. It did not recognize fibril-forming collagens or bind to GFOGER or other similar motifs in triple-helical peptides. No GFOGER motifs were found in Ciona collagens. As Ciona alpha1I bound to collagen IX, we propose that before the emergence of GFOGER-dependent collagen receptors in vertebrates, alphaI domain integrins might have been able to bind to collagen with alternative mechanisms.


Asunto(s)
Ciona intestinalis/clasificación , Ciona intestinalis/genética , Colágeno/metabolismo , Evolución Molecular , Integrinas/fisiología , Secuencia de Aminoácidos , Animales , Colágeno/química , Secuencia Conservada , Humanos , Enlace de Hidrógeno , Integrinas/química , Integrinas/genética , Modelos Moleculares , Datos de Secuencia Molecular , Oligopéptidos/química , Oligopéptidos/metabolismo , Conformación Proteica , Alineación de Secuencia
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