Vitamin D Receptor FokI, ApaI, and TaqI Polymorphisms in Lead Exposed Subjects From Saudi Arabia.

Vitamin D receptor (VDR) gene polymorphisms were reported to influence blood lead levels (BLL) and the response of subjects to the symptoms of lead toxicity. However, no studies have been conducted in the Saudi Arabian population which has unique ethnicity and socio-demographic features. This study examined the polymorphisms in exon 2 (allele 1) and intron 8 (allele 2 and allele 3) of VDR gene and their relation to BLLs. As per the CDC guidelines, the recruited lead-exposed workers (N = 130) were categorized to two groups viz., low BLL group (<10 µg/dL) and high BLL group (>10 µg/dL). The low BLL group had a mean BLL of 4.37 µg/dL, while the high BLL group had levels of 18.12 µg/dL (p < 0.001). Overall, the genetic variants, TC and CC in the VDR FokI were significantly associated with a risk of lead toxicity and the allele "C" was a risk factor (p = 0.00026). Furthermore, the TT genotype of VDR ApaI significantly increased the risk of developing lead poisoning (p = 0.0006). The VDR TaqI SNP was not significantly associated with lead toxicity. The highest BLLs for VDR FokI-CC, VDR ApaI-GG, and VDR TaqI-TT genotypes from High BLL group were 18.42, 15.26, and 18.75 µg/dL, respectively. Older age (51-60 years) was found to be a significant confounding factor for BLLs (p = 0.012). Additional studies in larger sample sizes are needed to firmly establish the role of VDR genotypes and genetic susceptibility to lead poisoning.

Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria.

Homocystinuria due to cystathionine beta synthase (CBS) deficiency results in elevated plasma homocysteine and methionine levels, which are associated with multiple organ pathologies, including vascular, respiratory, musculoskeletal, nervous, and ocular tissues. This autosomal recessive disorder is caused by homozygous or compound heterozygous mutations in the CBS gene encoding for the CBS. Although homocystinuria is observed in Arab and North African patients, their clinical presentations have not been described and molecular causes remained largely uninvestigated. In this study, we describe the clinical presentations of 22 homocystinuria patients from 13 Saudi Arabian families and 1 North African Sudanese family. Cardinal biochemical features of homocystinuria manifested in all patients, but heterogeneity of expression was observed for other associated phenotypes. One patient developed Legg-Calvé-Perthes disease that has not been previously described in homocystinuria. In the Saudi families, a novel nonsense mutation, p.Trp323X, and recurrent p.Arg336Cys and p.Gly153Arg mutations were identified in the CBS gene. The p.Trp323X mutation was found in 10 of the 13 unrelated Saudi families. In the Sudanese family, the p.Thr257Met mutation in the CBS gene, previously described in Italian and Spanish patients, was found. This study shows that the spectrum of CBS gene mutations in Saudi homocystinuria patients is quite different than the Arab patients from Qatar and Israel. This study is the only detailed phenotypic and genetic depiction of homocystinuria patients from Saudi Arabia and Sudan. The data are useful for diagnosis and management of Saudi patients.

Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.

Autoimmune polyendocrinopathy syndrome type 1 (APS1) is characterized by the presence of at least two out of three clinical features, which include Addison's disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. This disorder is caused by mutations in the AIRE (autoimmune regulator) gene. While several AIRE mutations have been described in APS1 patients of various ethnic origins, the genetic cause of APS1 in Arab patients requires further investigation. This study describes seven Arab families, in which 18 patients had APS1. In addition to the cardinal features of APS1, some patients exhibited alopecia, diabetes mellitus, nephrocalcinosis and other phenotypes associated with APS1. DNA sequencing of the AIRE gene of patients from this study identified four novel and one recurrent mutation. These mutations likely result in loss of AIRE function in the patients. In addition, it was noted that the non-pathogenic c.834C> G mutation (rs1800520, encoding for p.Ser278Arg) occurs with high incidence in the AIRE gene of Arab individuals. Furthermore, this investigation demonstrates inflammation of the hair follicles in APS1 patients with alopecia universalis. We conclude that Arab APS1 patients carry novel and recurrent mutations in the AIRE gene.

A family exhibiting arterial tortuosity syndrome displays homozygosity for markers in the arterial tortuosity locus at chromosome 20q13.

Arterial tortuosity associated with hyperextensible skin and hypermobility of joints, features that are characteristics of Ehlers-Danlos syndrome (EDS), has been described in several families. An arterial tortuosity locus has recently been mapped to chromosome 20q13. Here, we report a consanguineous Kurdish family in which an affected child manifested elongation and severe tortuosity of the aorta, carotid, and other arteries. Additional clinical symptoms include loose skin, hypermobile joints, hernias, and facial features that resemble EDS individuals. To examine whether the arterial tortuosity locus was involved in this child, homozygosity analysis was performed using microsatellite markers on 20q13. The affected child was found homozygous, whereas the unaffected parents and three siblings were heterozygous. Additional typing defined the genomic interval to a 37-cm region within which the arterial tortuosity locus is located. Three functional candidate genes (B4GALT5, KCNB1, and PTGIS) were sequenced. No mutations were discovered in the coding regions of these three genes and the promoter regions of B4GALT5 and KCNB1 genes. Moreover, the B4GALT5 mRNA expression was unaltered in patient-derived lymphoblastoid cells. In the PTGIS gene promoter, the affected child was homozygous for eight variable number of tandem repeats, while parents and unaffected siblings carried six repeats.

[Arterial tortuosity syndrome]. / Das Arterial-Tortuosity-Syndrom.

The arterial tortuosity syndrome is a rare congenital disorder characterized by elongation and generalized tortuosity of the major arteries including the aorta. Associated clinical features consist of excessively stretchable skin and joint laxity which is indicative of a connective tissue disorder such as Ehlers-Danlos or Cutis laxa syndrome. The gene locus of the arterial tortuosity syndrome has recently been localised on chromosome 20q13; inheritance ist autosomal recessive. - We report on a newborn with arterial tortuosity syndrome and hiatal hernia, bilateral hip dislocation, inguinal hernias and diffuse tortuosity of the great arteries including the aorta. Known gene loci involved in Ehlers-Danlos syndrome, cutis laxa syndrome and other connective tissue disorders were excluded by specific DNA markers. By homozygosity mapping with polymorphic microsatellite markers it was possible to confirm the gene locus for the ATS on chromosome 20q13. In addition to the presentation of this patient, a review of the literature is presented.

Fine mapping of the X-linked split-hand/split-foot malformation (SHFM2) locus to a 5.1-Mb region on Xq26.3 and analysis of candidate genes.

Split-hand/split-foot malformation (SHFM) is a genetically heterogeneous disorder, with five known loci, that causes a lack of median digital rays, syndactyly, and aplasia or hypoplasia of the phalanges, metacarpals, and metatarsals. In the only known SHFM2 family, affected males and homozygous females exhibit monodactyly or bidactyly of the hands and lobster-claw feet. This family (1) was revisited to include additional subjects and genealogical data. All 39 affected males and three females fully expressed the SHFM, while 13 carrier females examined exhibited partial expression of SHFM. We narrowed the previously linked 22-Mb genetic interval on Xq24-q26 (2), by analyzing additional family members and typing additional markers. The results define a 5.1-Mb region with a new centromeric boundary at DXS1114 and a telomeric boundary at DXS1192. We did not identify mutations in the exons and exon/intron boundaries of 19 candidate genes. These data suggest that the mutation may lie in a regulatory region of one of these candidate genes or in another gene within the SHFM2 region with unclear role in limb development.

Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).

Multiple hereditary exostoses (HME) is an autosomal dominant developmental disorder exhibiting multiple osteocartilaginous bone tumors that generally arise near the ends of growing long bones. Here, we report two large consanguineous families from Pakistan, who display the typical features of HME. Affected individuals also show a previously unreported feature--bilateral overriding of single toes. Analysis using microsatellite markers for each of the known EXT loci, EXT1, EXT2, and EXT3 showed linkage to EXT1. In the first family, mutation analysis of the EXT1 gene revealed that affected individuals were heterozygous for an in-frame G-to-C transversion at the conserved splice donor site in intron 1. This mutation is predicted to disrupt splicing of the first intron and produce a frameshift that leads to a premature termination codon. In the second family, an insertion of an A in exon 8 is predicted to produce a frameshift at codon 555 followed by a premature termination, a further 10 codons downstream. In both families, an increased number of affected male subjects were observed. In affected females in family 2, phenotypic variability and incomplete penetrance were noted.

The locus responsible for horizontal gaze palsy/progressive scoliosis and brainstem hypoplasia is refined to a 9-cM region on chromosome 11q23.

Horizontal gaze palsy associated with progressive scoliosis (HGPS) is a rare autosomal recessive condition that has been recently mapped to a 30-cM region on chromosome 11q23-25. In this report, we describe a consanguineous family in which three of five sibs are affected with HGPS. In two of the affected sibs, there was significant cognitive delay in addition to congenital horizontal gaze palsy and childhood onset scoliosis. In all three affected sibs, magnetic resonance imaging (MRI) scans revealed brainstem hypoplasia, a finding that has recently been associated with HGPS. Clinical examination of the family showed no significant dysmorphic features, while karyotyping, EMG, nerve conduction, and muscle biopsies were unrevealing. Homozygosity mapping was performed to narrow the disease locus on 11q23-25. A recombination event was observed in one affected sib between markers D11S1345 and D11S4464, which further refined the region to a 9-cM interval. Since the MRI results provide support for the theory that maldevelopment of neurons in the abducens nuclei and caudal longitudinal fascicle is the cause for HGPS, we speculate on the existence of a gene in this 9-cM interval on chromosome 11q23, which is critical for brainstem development.

Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism.

Cherubism is a rare autosomal dominant inherited condition caused by mutations in the c-Abl-binding protein SH3BP2. It is characterized by multiple cystic giant cell lesions of the jaw appearing in early childhood with stabilization and remission after puberty. In the present study, we used direct sequence analysis of the SH3BP2 gene of several individuals from a family with cherubism to search for additional SH3BP2 mutations resulting in cherubism. In affected relatives, we found a previously unreported G to A transition in exon 9 leading to a Gly to Arg substitution at amino acid position 420. G420R has been reported previously with a G to C transversion. To date there have been no disease causing mutations outside exon 9. Therefore, the amino acid sequence from positions 415 to 420 may represent a specific protein domain which, when disrupted, leads to the cherubism phenotype.

Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome).

The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait. All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones. Obligate heterozygote parents were phenotypically normal. Mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene have been reported in two acromesomelic chondrodysplasias (i.e. Hunter-Thompson type and Grebe type) which are phenotypically related to DuPan syndrome. CDMP1, a member of the transforming growth factor beta super-family of secreted signalling molecules, has been reported to regulate limb patterning and distal bone growth. Therefore, the present authors examined genomic DNA from the family with DuPan syndrome for mutations in the CDMP1 gene. Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene. This mutation was not found in 44 control subjects of Pakistani origin. The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein. This is likely to cause a conformational change in the CDMP1 protein that influences the expression of genes which are required for normal bone development. This finding extends the spectrum of phenotypes produced by defects in the CDMP1 gene.

Linkage mapping of a nonspecific form of X-linked mental retardation (MRX53) in a large Pakistani family.

Nonspecific X-linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X-linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2-26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081.

Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity.

A new syndromic form of X-linked mental retardation associated to obesity, MRXS7, has been localised to Xp11.3-Xq23 in a large Pakistani family. The ten affected males show clinical manifestations of mental retardation, obesity and hypogonadism. The family was genotyped by a set of microsatellite markers spaced at approximately 10 cM intervals on the X chromosome. Linkage to five adjacent microsatellite markers, mapping in the pericentromeric area, was established and a maximum two-point lod score of 3.86 was reached at zero recombination with marker DXS1106. Reduced recombination events around the centromere prevented precise mapping of the gene.

Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family.

Congenital atrichia is a rare form of hereditary human hair loss, characterized by the complete shedding of hair shortly after birth, together with the formation of papular lesions on the skin. Recently, we cloned the human homolog of the mouse hairless gene and identified pathogenic mutations in several families with inherited congenital atrichia. Here, we present the genomic organization of the human hairless gene (HGMW-approved symbol HR), which spans over 14 kb on chromosome 8p12 and is organized into 19 exons. In addition, we report the identification of a 22-bp deletion mutation in exon 3 of the hairless gene in a large consanguineous Arab Palestinian family from a village near Jerusalem, Israel. These findings extend the body of evidence implicating mutations in the hairless gene as an underlying cause of congenital atrichia in humans.

Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse.

The osteochondrodysplasias are a genetically heterogeneous group of disorders affecting skeletal development, linear growth and the maintenance of cartilage and bone. We have studied a large inbred Pakistani family with a distinct form of recessively inherited spondyloepimetaphyseal dysplasia (SEMD) and mapped a gene associated with this dwarfing condition to chromosome 10q23-24, a region syntenic with the locus for the brachymorphic mutation on mouse chromosome 19. We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes. We characterized a nonsense mutation in ATPSK2 in the SEMD family and a missense mutation in the region of Atpsk2 encoding the APS kinase activity in the brachymorphic mouse. ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell types. The cartilage-specificity of the human and mouse phenotypes provides further evidence of the critical role of sulfate activation in the maturation of cartilage extracellular matrix molecules and the effect of defects in this process on the architecture of cartilage and skeletogenesis.

Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred.

We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings.