Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme alpha-L-iduronidase (IDUA). The disease has severe and milder phenotypic subtypes. The IDUA mutations in five MPS I patients from three unrelated families from central and southern Tunisia were determined by amplifying and sequencing each of the IDUA exons and intron-exon junctions. Two novel IDUA mutations, c.1805delTinsGAACA in exon 13 and I270S in exon 7, and two previously reported mutations, P533R and R628X, were detected. The two patients in family 1 who had the Hurler phenotype were homoallelic for the novel deletion-insertion mutation. The patient in family 2 who also had the Hurler phenotype was heteroallelic for the novel missense mutation I270S and the previously reported nonsense mutation R628X. The two patients in family 3 who had the Hurler-Scheie phenotype were homoallelic for P533R. In addition, six known IDUA polymorphisms were identified. These are the first Tunisian MPS I patients to be genotyped. The identification of these mutations and their genotype-phenotype correlations should facilitate prenatal diagnosis and counselling for MPS I in Tunisia, where a very high rate of consanguinity exists.

Mucopolysaccharidosis type IVA (MPS IVA; OMIM #253000) or Morquio A syndrome is an autosomal recessive inborn error resulting from the deficient activity of the lysosomal enzyme, N-acetylgalactosamine-6-sulfatase (GALNS), and the progressive lysosomal accumulation of sulfated glycosaminoglycans. Clinically, the severe form of this lysosomal storage disease is characterized by a characteristic severe bone dysplasia and normal intelligence. To date, a variety of mutations have been associated with the severe MPS IVA phenotype. Here, we report the GALNS mutations in six severe MPS IVA patients from four unrelated Tunisian families. For mutation detection, each of the 14 exons and adjacent intron-exon junctions of the GALNS gene were sequenced after PCR-amplification from genomic DNA. Two novel mutations were identified: a G to A transition in the conserved 5' donor splice site of intron 1 (GACgt-->GACat: designated IVS1(+1g-->a)) and a G to C transversion in codon 66 of exon 2 predicting a glycine to arginine substitution (G66R). The IVS1(+1g-->a) mutation was homozygous in five similarly affected patients from three presumably unrelated families, but haplotype analysis suggested a common ancestor. The affected patient in the fourth family was homozygous for the G66R mutation. These are the first GALNS mutations causing severe MPS IVA disease identified in Tunisia. These molecular findings provide genotype/phenotype correlations, and permit accurate carrier detection, prenatal diagnosis, and counseling for MPS IVA disease in Tunisia where first cousin consanguineous mating remains frequent.

Background: Congenital fibrosis of the extraocular muscles (CFEOM) is a heterogeneous group of disorders that may be associated with other anomalies. The association of a CFEOM syndrome with ulnar hand abnormalities (CFEOM/U) has not been reported to date. Objective: To describe a new autosomal recessive syndrome of CFEOM and ulnar hand abnormalities, and localise the disease causing gene. Methods: Clinical evaluation of the affected members and positional mapping. Results: Six affected patients with CFEOM/U (aged 2 to 29 years) from a large consanguineous Turkish family were studied. Ophthalmological involvement was characterised by non-progressive restrictive ophthalmoplegia with blepharoptosis of the right eye. The postaxial oligodactyly/oligosyndactyly of the hands was more severe on the right side. A genome-wide scan established linkage of this new autosomal recessive syndrome to a locus on chromosome 21qter. The multipoint LOD score was 4.53 at microsatellite marker D21S1259, and fine mapping defined a ∼1.5 Mb critical region between microsatellite marker D21S1897 and the telomere of the long arm. Conclusions: CFEOM/U maps to a 1.5 Mb region at chromosome 21qter. Future identification of the disease causing gene may provide insights into the development of the extraocular muscles and brain stem α motor neurones, as well as anteroposterior limb development.

Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and 1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15 mutations account for the higher prevalence of CD in AJ individuals, the haplotypes and allele frequencies of the common mutations and variants were assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246 AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ patients from multiplex families with CD from Central (44.0%) versus Eastern (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%) compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the frequency of the common mutations was slightly lower in AJ patients with CD (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with both the P268 and 268S alleles. CARD15 mutation frequencies were greater in affected sib pairs than in sporadic CD cases but actually decreased in families with three or more affected sibs, raising the possibility of genetic heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in the families with three or more affected sibs compared with sib pairs. Screening the CARD15 gene for rare variants revealed five novel changes (D113N, D357A, I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may be disease predisposing. Also, there was no evidence for increased risk associated with the recently described IVS(+158) single-nucleotide polymorphism. Although the AJ controls appear to have a higher frequency of CARD15 mutations than the SOJ controls, it is unlikely that this difference fully explains the excess frequency of CD in the AJ population.

Type I Waardenburg syndrome (WS-I) is an auditory-pigmentary syndrome caused by heterozygous loss of function mutations in the PAX3 gene. Klein-Waardenburg syndrome (WS-III) is a very rare condition and represents an extreme presentation of WS-I, additionally associated with musculoskeletal abnormalities. We present an 18-months old Turkish child with typical Klein-Waardenburg syndrome (WS) including dystopia canthorum, partial albinism, and upper-limb defects. The child was born to a consanguineous couple and both parents had WS-I. We screened the entire coding region of the PAX3 gene for mutations and identified a novel missense mutation, Y90H, within the paired box domain of PAX3. Both parents were heterozygous for the mutation and the proposita was homozygous. This is the third report of a homozygous PAX3 mutation causing the WS-III phenotype. Molecular analysis of four additional Turkish families with variable clinical expression of WS-I identified two missense mutations, one splice-site mutation, and one small insertion in the PAX3 gene.

We analyzed the insulin receptor gene in four patients with leprechaunism and one with type A insulin resistance. We detected novel and previously reported mutations. The novel mutants were expressed in Chinese hamster ovary cells to evaluate the consequences for insulin receptor function. A type A insulin resistance patient from Morocco was homozygous for Arg252His mutation, similar to a previously described type A patient from Japan. A patient with leprechaunism was homozygous for the Ser323Leu mutation, previously identified in homozygous form in two patients with Rabson-Mendenhall syndrome. Phenotypic expression of this mutation is variable. A patient with leprechaunism is compound heterozygous for the previously described Arg1092Trp mutation and a nonsense mutation in codon 897. Another patient with leprechaunism was homozygous for a novel Asn431Asp mutation, which only partially reduces insulin proreceptor processing and activation of signaling cascades. The novel Leu93Gln mutation that fully disrupts proreceptor processing was found in one allele in a patient with leprechaunism. A nonsense mutation at codon 1122 was in the other allele. These results expand the number of pathogenic insulin receptor mutations and demonstrate the variability in their phenotypic expression. The biochemical analysis of mutant insulin receptors does not reliably predict whether the phenotype will be leprechaunism, the Rabson-Mendenhall syndrome, or type A insulin resistance. The previously reported correlation between fibroblast insulin binding and duration of patient survival was not observed.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a vonWillebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.

21-Hydroxylase deficiency is a recessively inherited disorder resulting from mutations in the CYP21 gene. The CYP21 gene is located along with the CYP21P pseudogene in the human leukocyte antigen major histocompatibility complex region on chromosome 6. Molecular diagnosis is difficult due to the 98% similarity of CYP21 and CYP21P genes and the fact that almost all frequently reported mutations reside on the pseudogene. Allele-specific PCR for the 8 most frequently reported point mutations was performed in 31 Turkish families with at least a single 21-hydroxylase-deficient individual. The allele frequencies of the point mutations were as follows: P30L, 0%; IVS2 (AS, A/C-G,-13), 22.5%; G110Delta8nt, 3.2%; I172N, 11.4%; exon 6 cluster (I236N, V237E, M239K), 3.2%; V281L, 0%; Q318X, 8%; and R356W, 9.6%. Large deletions and gene conversions were detected by Southern blot analysis, and the allele frequencies were 9.6% and 22.5%, respectively. Sequence analysis of the gene, performed on patients with only 1 mutated allele, revealed 2 missense mutations (R339H and P435S). A novel semiquantitative PCR/enzyme digestion-based method for the detection of large scale deletions/conversions of the gene was developed for routine diagnostic purposes, and its accuracy was shown by comparison with the results of Southern blot analysis.

We present a large Turkish family with autosomal dominant inherited ulnar-mammary syndrome in which 10 affected family members, spanning three generations, were diagnosed. The phenotypic expression of the disease was found to be highly variable among the affected family members showing posterior-limb deficiencies and/or duplications, mammary-gland hypoplasia, apocrine dysfunction, dental and genital abnormalities. Mutation analysis of the TBX3 gene showed a novel one base-pair insertion at position 89 (designated 88_89insA) in the coding region. The mutation leads to a shift of the open reading frame and causes a premature truncation of the protein (M30fsX110). The truncated protein lacks almost all functional important parts of TBX3, most likely leading to a complete loss of functional protein. Our findings indicate that ulnar-mammary syndrome shows a wide range of phenotypes even within the same family and provide further evidence that haploinsufficiency of TBX3 is the disease-causing mechanism.

Childhood‐onset spinal muscular atrophy (SMA) is one of the most common neurodegenerative genetic disorders. SMN1 is the SMA‐determining gene deleted or mutated in the majority of SMA cases. There is no effective cure or treatment for this disease yet. Thus, the availability of prenatal testing is important. Here we report prenatal prediction for 68 fetuses in 63 Turkish SMA families using direct deletion analysis of the SMN1 gene by restriction digestion. The genotype of the index case was known in 40 families (Group A) but unknown in the remaining 23 families (Group B). A total of ten fetuses were predicted to be affected. Eight of these fetuses were derived from Group A and two of these fetuses were from Group B families. Two fetuses from the same family in Group A had the SMNhyb1 gene in addition to homozygous deletion of the NAIP gene. One fetus from Group A was homozygously deleted for only exon 8 of the SMN2 gene, and further analysis showed the presence of both the SMN1 and SMNhyb1 genes but not the SMN2 gene. In addition, one carrier with a homozygous deletion of only exon 8 of the SMN1 gene was detected to have a SMNhyb2 gene, which was also found in the fetus. To our knowledge, these are the first prenatal cases with SMNhyb genes. Follow‐up studies demonstrated that the prenatal predictions and the phenotype of the fetuses correlated well in 33 type I pregnancies demonstrating that a careful molecular analysis of the SMN genes is very useful in predicting the phenotype of the fetus in families at risk for SMA. Copyright © 2002 John Wiley & Sons, Ltd.

Dominant mutations in the GJB2 gene encoding connexin 26 (Cx26) can cause non‐syndromic hearing impairment alone or in association with palmoplantar keratoderma (PPK). We have identified the novel G224A (R75Q) mutation in the GJB2 gene in a four‐generation family from Turkey with autosomal dominant inherited hearing impairment and PPK. The age of onset and progression of hearing loss were found to be variable among affected family members, but all of them had more severe impairment at higher hearing frequencies. Interestingly, the novel R75Q mutation affects the same amino acid residue as described recently in a small family (R75W) with profound prelingual hearing loss and PPK. However, the R75W mutation was also observed in a control individual without PPK and unknown hearing status. Therefore, the nature of the R75W mutation remains ambiguous. Our molecular findings provide further evidence for the importance of the conserved R75 in Cx26 for the physiological function of the inner ear and the epidermal cells of the skin.

Hereditary spastic paraplegia (HSP) is a degenerative neurologic disorder that causes progressive, often severe, spastic weakness in the legs. Autosomal dominant HSP is a highly penetrant, genetically heterogeneous disorder with loci present on chromosomes 2p21-24, 2q24-34, 8q23-24, 10q23.3-24, 12q13, 14q12-23, 15q11-14 and 19q13.1. We identified a large HSP kindred in which the disorder was tightly linked to chromosome 14q12-23. We tested chorionic villus DNA samples of two at-risk fetuses for inheritance of microsatellite polymorphisms flanking and within this locus that segregated with the disease in this family. Whereas samples from the first fetus showed inheritance of a haplotype segregating with the disease allele (indicating high risk of developing HSP), samples from the second fetus showed inheritance of a haplotype segregating with the normal allele (indicating low risk of developing HSP). This is the first report of prenatal testing for HSP. Published in 2001 by John Wiley & Sons, Ltd.

We report a unique glycine substitution in type I collagen and highlight the clinical and biochemical consequences. The proband is a 9 year old Turkish boy with severely deforming osteogenesis imperfecta (OI). Biochemical analysis of (pro) collagen type I from a skin fibroblast culture showed both normal and overmodified alpha chains. Molecular analysis showed a G>T transversion in the COL1A2 gene, resulting in the substitution of glycine by tryptophan at position 277 of the alpha2(I) collagen chain. Glycine substitutions in type I collagen are the most frequent cause of the severe and lethal forms of OI. The phenotypic severity varies according to the nature and localisation of the mutation. Substitutions of glycine by tryptophan, which is the most voluminous amino acid, have not yet been identified in type I collagen or any other fibrillar collagen. The severe, though non-lethal OI phenotype associated with this mutation may appear surprising in view of the huge size of the tryptophan residue. The fact that the mutation resides within a so called "non-lethal" region of the alpha2(I) collagen chain supports a regional model in phenotypic severity for alpha2(I) collagen mutations, in which the phenotype is determined primarily by the nature of the collagen domain rather than the type of glycine substitution involved.

We evaluated the frequency of renal malformations in relation to nonmosaic 45,X (group A, 45 patients, 54.9%) and mosaic/structural abnormalities of X (group B, 37 patients, 45.1%) in 82 Turkish patients with Turner syndrome (TS). Ultrasonography of the kidneys and collecting system was performed in all patients. Of the 82 patients, 31 had different renal malformations (37.8%). Horse-shoe kidney was observed in 9 (29.0%) of the 31 patients, and 17 patients (54.8%) had various collecting system malformations, while 5 (16.2%) had malrotation and other positional abnormalities. The prevalence of renal malformations was significantly higher in group A (51.1%) than group B (21.6%) (2:7.94, P<0.05). Although 8 of the 9 patients with horse-shoe kidney had the 45,X karyotype, collecting system malformations were observed more frequently in group B. Recurrent urinary tract infections (UTIs) were detected during follow-up in 7 patients, and hypertension developed in 3 patients. In patients who had a normal baseline nephrological evaluation, no problem suggesting renal disease developed during follow-up. We conclude that all forms of TS should have routine nephrological screening on diagnosis, since structural malformations of the kidney occur more frequently in nonmosaic 45,X TS, while collecting system malformations are mostly seen in mosaic/structural X forms. Those included in the group for nephrological follow-up had an increased risk for hypertension and/or UTI.

Ultrasound in Obstetrics & GynecologyVolume 13, Issue 1 p. 75-76 Letter to the EditorFree Access Prenatal sonographic diagnosis of type I achondrogenesis with a large cystic hygroma S. Özeren, Corresponding Author S. Özeren Department of Obstetrics and Gynecology, School of Medicine, University of Kocaeli, TurkeyDepartment of Obstetrics and Gynecology, School of Medicine, University of Kocaeli, TurkeySearch for more papers by this authorA. Yüksel, A. Yüksel Department of Obstetrics and Gynecology, School of Medicine, University of Istanbul, TurkeySearch for more papers by this authorT. Tükel, T. Tükel Institute of Child Health, School of Medicine, University of Istanbul, TurkeySearch for more papers by this author S. Özeren, Corresponding Author S. Özeren Department of Obstetrics and Gynecology, School of Medicine, University of Kocaeli, TurkeyDepartment of Obstetrics and Gynecology, School of Medicine, University of Kocaeli, TurkeySearch for more papers by this authorA. Yüksel, A. Yüksel Department of Obstetrics and Gynecology, School of Medicine, University of Istanbul, TurkeySearch for more papers by this authorT. Tükel, T. Tükel Institute of Child Health, School of Medicine, University of Istanbul, TurkeySearch for more papers by this author First published: 23 December 2002 https://doi.org/10.1046/j.1469-0705.1999.13010075.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume13, Issue11 January 1999Pages 75-76 RelatedInformation