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Biomedical subjects

M Mottes

Publications and source records attributed to M Mottes.

At least 19 recordsLinked to original sources
PubMed2006

Osteogenesis imperfecta: clinical, biochemical and molecular findings.

Mutations in COL1A1 and COL1A2 genes, encoding the alpha1 and alpha2 chain of type I collagen, respectively, are responsible for the vast majority of cases of osteogenesis imperfecta (OI) (95% of patients with a definite clinical diagnosis). We have investigated 22 OI patients, representing a heterogeneous phenotypic range, at the biochemical and molecular level. A causal mutation in either type I collagen gene was identified in 20 of them: no recurrent mutation was found in unrelated subjects; 15 out of 20 mutations had not been reported previously. In two patients, we could not find any causative mutation in either type I collagen gene, after extensive genomic DNA sequencing. Failure of COL1A1/COL1A2 mutation screening may be due, in a few cases, to further clinical heterogeneity, i.e. additional non-collagenous disease loci are presumably involved in OI types beyond the traditional Sillence's classification.

Adolescent↗
PubMed2005

Osteoporosis in beta-thalassemia: Clinical and genetic aspects.

Osteoporosis and osteopenia are frequent complications of thalassemia major (TM) and intermedia (TI). Osteoporosis was found in 23/25 patients with TI and in 115/239 patients with TM. In TM, no association was found with specific polymorphisms in candidate genes (vitamin D receptor, estrogen receptor, calcitonin receptor, and collagen type 1 alpha 1). Osteoporosis in female patients with TM was strongly associated with primary amenorrhea (P < .0001), while in male patients with TM, hypogonadism was not significantly related to bone mineral density (BMD) (P = .0001). Low BMD was also associated with cardiomiopathy (P = .01), diabetes mellitus (P = .0001), chronic hepatitis (P = .0029), and increased ALT (P = .01).

Adult↗
PubMed2002

Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass, bone turnover markers, and sex hormones in men.

Osteoporosis is a disease characterized by low bone mineral density (BMD) and up to 80% of its variance is under genetic control. Although osteoporosis is more frequent in women, one-third of hip fractures also occur in men. Much information on genetic factors and bone density has been obtained in women, but only a few studies have been performed in osteoporotic men. We have evaluated the relationship between polymorphisms for several candidate genes such as vitamin D receptor (VDR), collagen type Ia1 (COLIA1), and calcitonin receptor (CTR) in a sample of unrelated Italian men (n = 253, mean age 58.41 +/- 15.64 SD). We found no significant differences in BMD when subjects were stratified for their VDR (BsmI and FokI) and COLIA1 genotypes. BMD both at the lumbar spine and at the femoral neck were associated with polymorphism of CTR gene. The CC genotype of CTR gene had the lowest BMD value (P <0.05 and P <0.01 at the spine and hip, respectively) and its prevalence was significantly over-represented in the subgroup of men with prior hip or vertebral fracture as compared with controls (P = 0.004% c2 = 11.10). The men with the CC genotype also showed significantly lower body mass index (BMI), serum sex hormone binding globulin (SHBG), estradiol, total alkaline phosphatase-(total AP) and bone alkaline phosphatase (bone AP) levels and significantly higher free androgen index (FAI). In conclusion, the polymorphism of CTR gene but not VDR and COLIA1 is associated with osteoporosis incidence and the levels of alkaline phosphatase and estradiol. The lower BMD in CC genotype is apparently associated in males with depressed bone formation and lower estradiol levels.

Adult↗
PubMed2002

Rapid and efficient genotype analysis of the COL1a1 Sp1 binding site dimorphism, a genetic marker for bone mineral density.

A biallelic G/T polymorphism within the first intron of COL1A1 gene at a recognition site for the transcription factor Sp1 has been shown to be significantly related to bone mass and osteoporotic fracture. To date this polymorphism has been detected by conventional genomic DNA amplification followed by restriction enzyme digestion and polyacrylamide gel electrophoresis. We have designed a rapid and efficient genotyping method based on allele-specific polymerase chain reaction

Binding Sites↗
PubMed2002

Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome.

The Stickler syndrome is among the most common heritable disorders of connective tissue. The syndrome fully expressed clinical phenotype includes the degeneration of the vitreous gel and retina, frequently associated with myopia, accompanied by non-ocular features, such as craniofacial dysmorphisms or malformations, hearing impairment, skeletal dysplasia and progressive arthropathy. So far, mutations at three collagen loci, COL2A1, COL11A1 and COL11A2, have been found in Stickler syndrome patients, with about two thirds of investigated familial cases found to be associated to COL2A1 gene mutations. We report on a three generation family in which a diagnosis of Stickler syndrome was made and linkage analysis suggested COL2A1 to be the causing gene. These data permitted us to perform two prenatal diagnosis analysing the 3'VNTR polymorphism of the involved gene on amniocytes' DNA and to provide the family with genetic counselling and paediatric support at the delivery.

Adolescent↗
PubMed2001

A novel 4-bp deletion creates a premature stop codon and dramatically decreases HEXB mRNA levels in a severe case of Sandhoff disease.

We present the molecular genetic analysis of an infantile-onset Sandhoff disease patient. Genomic DNA amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 (497 DeltaAGTT). The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels.

Base Sequence↗
PubMed2001

Stickler syndrome and vitreoretinal degeneration: correlation between locus mutation and vitreous phenotype. Apropos of a case.

BACKGROUND: Autosomal dominant vitreoretinopathies are characterized by genetic heterogeneity. Structural mutations in COL2A1 are the most frequent cause of Stickler syndrome with ocular involvement. The affected patients have a characteristic vitreous alteration, so-called membranous vitreous, or type 1 vitreous phenotype. Recently a novel mutation in the gene encoding the alpha 1 chain of type XI collagen (COL11A1) was reported in rare Stickler pedigrees, with a different, so-called beaded or type 2 vitreous phenotype. METHODS: Five patients of an Italian family affected by high myopia, high frequency of retinal detachment, and other systemic stigmata evocative of Stickler syndrome (flat midface, depressed nasal bridge, short nose, spondyloepiphyseal dysplasia and osteoarthritis) were studied. Genetic investigations were also performed, considering three candidate loci for Stickler syndrome and Wagner syndrome (COL2A1, COL11A1, WGN1). RESULTS: Segregation analysis was performed utilizing polymorphic markers. COL2A1 and WGN1 segregations were excluded; COL11A1 showed concordance with the disease. The vitreous phenotype of the family was a typical type 1 or "membranous" vitreous, although all the previously reported COL11A1-related Stickler syndromes had always shown the type 2 or "beaded" vitreous phenotype. CONCLUSIONS: The clear presence of the type 1 or "membranous" vitreous phenotype in our family, despite the probable mutation in the COL11A1 gene, suggests greater phenotypical heterogeneity and a more extensive mutation spectrum, even of the COL11A1 gene, than previously thought, explaining the basis for the different vitreous phenotypes seen in Stickler syndrome.

Child↗
PubMed2001

Osteogenesis imperfecta at the beginning of bone and joint decade.

Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by increased bone fragility. Four different types of the disease are commonly distinguished, ranging from a mild condition (type I) to a lethal one (type II). Types III and IV are the severe forms surviving the neonatal period. In most cases, there is a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes. These classic forms of OI are described in this review. There are instances, however, where alterations in bone matrix components, other than type I collagen, are the basic abnormalities of the OI. Recently, three such discrete types have been identified by histomorphometric evaluation (types V and VI) and linkage analysis (Rhizomelic OI). They provide evidence for the as yet poorly understood complexity of the phenotype-genotype correlation in OI. We also discuss bisphosphonates treatment as well as fracture management and surgical correction of deformities observed in the patients with OI. However, ultimately, strengthening bone in OI will involve steps to correct the underlying genetic mutations that are responsible for this disorder. Thus, we also describe different genetic therapeutic approaches that have been tested either on OI cells or on available OI murine models.

Animals↗
PubMed2000

Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. On the basis of recent evidence of locus heterogeneity, we studied 19 subjects (7 affected members) of a BRIC family. Male-to-male transmission and the presence of affected females suggested autosomal dominant inheritance. Blood samples were collected after informed consent. Subjects were genotyped by using markers mapping to 18q and 2q24 region, respectively, where the genes FIC1 and FIC2 have been mapped. Segregation of haplotypes excluded the two regions in our family. These findings suggest further genetic heterogeneity of the origin of BRIC.

Adenosine Triphosphatases↗
PubMed2000

Detection of mutations in the ALD gene (ABCD1) in seven Italian families: description of four novel mutations.

The study describes the mutations causing adrenoleukodystrophy in seven Italian families. Four missense mutations leading to amino acid substitutions, two frameshift mutations leading to a premature termination signal, and a splicing mutation were identified. Mutations 2014C>T (P543L), 2053A>G (Q556A), 673-674insCC, and 1874+1G>A are described for the first time in this report. Mutations 1638C>T (R418W), 1588G>A(R401Q), and 1801-1802delAG are already known to be link to ALD.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2000

Three novel polymorphic sequence variants in the type I collagen gene COL1A1, the main disease locus for Osteogenesis Imperfecta.

Three novel polymorphic variants were found within COL1A1 genomic sequence (accession number AF017178) while screening several patients in the search of OI causal mutations. The three polymorphisms, located in intron 12, exon 26, and intron 29, respectively, can be detected by PCR amplification and digestion with appropriate restriction enzymes (Mbo II, Bst NI, Pvu II, respectively). Allelic frequencies within the Italian population were calculated.

Base Sequence↗
PubMed2000

Association of CTR and COLIA1 alleles with BMD values in peri- and postmenopausal women.

The variability of bone mass and bone strength is in part genetically determined. The pathophysiology of the disease is complex and its heritability is almost certainly polygenic. In a large group of women from north eastern Italy, homogeneous for calcium intake and other risk factors for osteoporosis, we investigated three different genetic polymorphic markers that have been associated with bone mineral density (BMD). The study includes 663 postmenopausal (aged 48-85 years) and 52 perimenopausal (aged 47-53 years) women. Lumbar spine and hip BMD were measured by dual energy X-ray absorptiometry (DXA). After DNA extraction, the restriction enzymes utilized were MscI for the SP1 site of the collagen type I regulatory region (COLIA1), AluI for the calcitonin receptor (CTR) gene, and BsmI for the Vitamin D receptor (VDR) gene. COLIA1 genotype was significantly associated with age-adjusted hip BMD, with the highest values in the SS group and the lowest in the ss group (p < 0.05). The COLIA1 effect was not visible until the sixth decade of life, but it increased thereafter with aging, becoming statistically significant also at the lumbar spine in subjects aged >70 years. CTR genotype was also significantly related to bone mass in the CC group, with the lowest age and weight-adjusted BMD values at the spine (p < 0.05). The CTR genotype effect was greater in the younger subset of women. This suggests that the CTR genotype might influence the process of acquiring peak bone mass rather than the process of bone loss along aging. No trend association was found between BMD values and VDR genotype. These findings suggest an association between the COLIA1 gene polymorphism more with the age-related rate of bone loss than with peak bone mass, which apparently is somewhat affected by CTR gene polymorphism.

Aged↗
PubMed1999

Two novel frameshift mutations in the adrenoleukodystrophy gene in Italian patients.

Two novel frameshift adrenoleukodystrophy mutations in two families were identified: a complex dinucleotide deletion/tetranucleotide insertion at 1116 TC-->GAGA (codon 244 [serine]) and an AG deletion at nucleotide 1462 (codon 359 [glutamic acid]). Both mutations are predicted to cause premature termination of protein synthesis. The patients were affected by childhood cerebral adrenoleukodystrophy and by adrenomyeloneuropathy with mild Addison disease, respectively.

Adrenoleukodystrophy↗
PubMed1999

Two novel missense mutations causing adrenoleukodystrophy in Italian patients.

The authors present two new missense mutations in exon 1 of the adrenoleukodystrophy (ALD) gene. The first, a C813T transition, results in the substitution Pro143 Ser in the third putative transmembrane domain of the adrenoleukodystrophy protein (ALDP) in an adult onset case. The second, a de novo C709T transition, results in a substitution Ser 108 Leu between the second and the third putative transmembrane segments, in a childhood case.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed1999

A novel intragenic polymorphism within the COL1A1 locus which can be detected by Taq I restriction of amplified genomic DNA.

A C-->T transition at nucleotide 9168 of COL1A1 genomic sequence (GenBank AF017178) was found in three unrelated patients, during the search for OI causal mutations. This polymorphic variant was then tested in the general population by Taq I restriction of genomic DNA amplified with a specifically designed restriction enzyme site-generating oligonucleotide primer. Allelic frequencies were found to be: 0.88 (C allele) and 0.12 (T allele), respectively.

Alleles↗
PubMed1998

Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online.

Van Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the HVL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant.

Genes, Tumor Suppressor↗
PubMed1998

Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.

Metachromatic leukodystrophy (MLD) is an autosomal recessive storage disease caused by deficiency of the lysosomal enzyme, arylsulfatase A. Two common mutations causing MLD have been characterized and correlations between phenotype and genotype have been established. A third common mutation, T799G, has also been identified in European MLD patients, and is associated with the late-onset forms of the disease. We report the molecular analysis of two Italian MLD patients, with juvenile and adult onset of the disease, respectively, who carried the T799G mutation in compound heterozygosity with different null mutations. A novel rapid mutation detection method is demonstrated for patient screening. One patient has a novel mutation, a T553C [corrected] transition that results in the substitution of Pro for Leu at codon 135, and produces no enzymatic activity in transfection experiments.

Adult↗