Gonadal function in two siblings with Fanconi's anemia

2 siblings with Fanconi's anemia, 1 male and 1 female, aged 22 and 24 years, respectively, were evaluated at the Johns Hopkins Hospital because of short stature and hypogonadism. Plasma levels of somatomedin-C were normal in both patients, suggesting that the production of biologically active growth hormone was normal in these subjects. In addition, measurements of serum gonadotropins and plasma androgens in our patients, along with data accumulated from previous studies in the literature, show that abnormal sexual development in patients with Fanconi's anemia is due to hypergonadotropic hypogonadism.     

Aspartylglycosaminuria in a non-Finnish patient caused by a donor splice mutation in the glycoasparaginase gene.

Aspartylglycosaminuria is a lysosomal storage disease caused by deficient activity of glycoasparaginase (EC 3.5.1.26), and it occurs with a high frequency among Finns. We have recently shown that the molecular defect in all Finnish aspartylglycosaminuria patients examined to date consists of two single base changes in the heavy chain of glycoasparaginase (Mononen, I., Heisterkamp, N., Kaartinen, V., Williams, J. C., Yates, J. R., III, Griffin, P. R., Hood, L. E., and Groffen, J. (1991) Proc. Natl. Acad. Sci U.S.A. 88, 2941-2945). This is the first report on the identification of the molecular defect causing aspartylglycosaminuria in a patient of non-Finnish origin. Total RNA from fibroblasts of a black American aspartylglycosaminuria patient was isolated, first-strand cDNA was synthesized, and the cDNA encoding glycoasparaginase was amplified by the polymerase chain reaction. The patient's mRNA nucleotide sequence was different from the normal sequence by a deletion of 134 nucleotides at positions 807-940. Nucleotide sequence analysis of the normal glycoasparaginase gene demonstrated that the deletion corresponded precisely to a 134-base pair exon. Moreover, analysis of the splice sites demonstrated a single base change, G to T, that altered the donor splice site of the exon deleted in the patient's mRNA. This change led to an exon-skipping event resulting in a frame shift and generation of a stop codon.     

Mohr syndrome in two siblings

The present study reports on two siblings of different sex, affected with a condition corresponding to Mohr syndrome. Characteristic symptoms such as epicanthic folds, a broad and flattened nasal root, a lobulated and hamartomatous tongue, poly- and syndactyly on both hands and feet, doubling of the big toes with less frequent features such as marked psychosomatic retardation and overall hypotony have been observed. All the cited anomalies have been of importance in the differential diagnosis. Difficulties associated with classification of new syndromes and the importance for practical clinical genetics of distinguishing between them are discussed.     

Dysmorphic face in two siblings with infantile neuroaxonal dystrophy

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive, neurodegenerative disease with onset in the first or second year of life. It has been reported that INAD shows numerous phenotype characteristics including problems associated with vision, hearing and physical coordination. It has however been very rare to see facial dysmorphism in these children. The study analyzes a girl and boy of a first cousin marriage with infantile neuroaxonal dystrophy affected at birth. At infancy, the children were examined in the Cerrahpa?a Medical Faculty Genetic Research Center, Istanbul. They had typical INAD features such as the lack of head control, vision, speech, sitting, and walking which are also seen in children with other congenital abnormalities. These children showed remarkable dysmorphism in the face which included prominent forehead, strabismus, small nose, fish mouth (boy), micrognathia, and large and low-settled ears. The presence of these facial features makes the patients appear unique and diagnosis more accurate. While these features are commonly seen diagnosis may be difficult at its onset. Until now this appearence has not been reported in INAD patients. In conclusion, in the first few months of life without any clinical or neurological signs, the physician should also consider diagnosing the disease of the infant as INAD.     

Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension

Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patient's family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.     

Partial trisomy 7q in two siblings

Trisomy for 7q32 leads to 7qter and monosomy for 9p24 leads to 9pter is observed in a sister and a brother, due to a balanced reciprocal translocation between the long arm of the chromosome 7 and the short arm of the chromosome 9 in the mother. The siblings are retarded mentally as well as in statomotoric development. This paper discusses the correlation between chromosomal states and certain deformities in patients with trisomies of different segments of 7q.     

Identification and analysis of a novel mutation in PEPD gene in two Kashmiri siblings with prolidase enzyme deficiency

Prolidase deficiency (PD) is a rare inborn disorder of collagen metabolism characterized by chronic recurrent cutaneous ulceration. We report a novel 3 bp insertion in the 12th exon of the PEPD gene in two Kashmiri siblings with prolidase deficiency phenotype. This mutation results in addition of an extra alanine residue at the amino-acid position number 304 of prolidase peptide. The structural analysis showed that this Ala insertion is located at the helix (a.a. 300–320), which contains several important hydrogen bonds between residues essential for structural folding for the enzyme activity. In silico analysis suggests that this insertion mutation might distort or bend the helical feature to affect the hydrogen-bond network between residues of neighboring secondary structures and deform the metal-binding geometry of the enzyme. Although approximately 70 PEPD gene mutations and polymorphisms have been reported in various ethnic groups, we however report, for the first time, the identification of insertion mutation in human the PEPD gene.     

Beta-alanine and beta-aminoisobutyric acid levels in two siblings with dihydropyrimidinase deficiency

Dihydropyrimidinase (DHP) deficiency is an inborn error of the pyrimidine degradation pathway, affecting the hydrolytic ring opening of the dihydropyrimidines. In two siblings with a complete DHP deficiency and a variable clinical presentation, a normal concentration of beta-alanine and strongly decreased levels of beta-aminoisobutyric acid were observed in plasma, urine and CSF. No major differences were observed for the concentrations of the beta-amino acids in plasma and urine between the symptomatic and asymptomatic sibling. Thus, the relevance of the shortage of beta-aminoisobutyric acid for the onset of a clinical phenotype in patients with DHP deficiency remains to be established.     

Splicing defect at the ornithine aminotransferase (OAT) locus in gyrate atrophy.

Gyrate atrophy (GA), a recessive eye disease involving progressive vision loss due to chorioretinal degeneration, is associated with the deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT), with consequent hyperornithinemia. We and others have reported a number of missense mutations at the OAT locus which result in GA. Here we report a GA patient of Danish/Swedish ancestry in whom one OAT allele produces an mRNA that is missing a single 96-bp exon relative to the normal mRNA. Polymerase-chain-reaction amplification and sequencing revealed a 9-bp deletion covering the splice acceptor region of exon 5, resulting in the absence of exon 5 sequences from the mRNA with no disruption to the reading frame. This mutation, which was not present in 15 other independent GA patients, adds to the array of allelic heterogeneity observed in GA and represents the first example of a splicing mutation associated with this disorder.     

Novel mutation at the initiation codon in the Norrie disease gene in two Japanese families

We have identified a new mutation of Norrie disease (ND) gene in two Japanese males from unrelated families; they showed typical ocular features of ND but no mental retardation or hearing impairment. A mutation was found in both patients at the initation codon of exon 2 of the ND gene (ATG to GTG), with otherwise normal nucleotide sequences. Their mothers had the normal and mutant types of the gene, which was expected for heterozygotes of the disease. The mutation of the initiation codon would cause the failure of ND gene expression or a defect in translation thereby truncating the amino terminus of ND protein. In view of the rarity and marked heterogeneity of mutations in the ND gene, the present apparently unrelated Japanese families who have lived in the same area for over two centuries presumably share the origin of the mutation.     

Dermatophytosis caused by Nannizzia nana in two siblings

Background

Nannizzia nana is a zoophilic dermatophyte that affects animals like pigs, boars and, exceptionally, humans, in whom it causes tinea capitis, as well as tinea corporis and onychomycosis.

Selective vitamin B12 malabsorption in two siblings

Two siblings with megaloblastic anemia responsive to parenteral vitamin B₁₂ were studied to elucidate the cause of the B₁₂ deficiency. Gastric juice from both contained acid and functional intrinsic factor. Serum contained transcobalamin II and lacked antibodies to intrinsic factor. Schilling tests showed vitamin B₁₂ malabsorption uncorrected by hog intrinsic factor or pancreatic extract. Other parameters of small intestinal function were normal. Proteinuria was initially present in both but cleared in one following treatment with B₁₂. These patients with “familial selective vitamin B₁₂ malabsorption” are the first reported from Canada. Only 37 cases have been reported in the world literature to date.     

Identification of one novel causative mutation in exon 4 of WFS1 gene in two Italian siblings with classical DIDMOAD syndrome phenotype

The aim of the present paper is to describe a novel missense mutation (G107R) of WFS1 gene that was unexpectedly detected, in two siblings from Southern Italy, outside exon 8; a very unusual finding which has previously been reported only twice in Italian patients with Wolfram syndrome (WS). Although in Spanish pedigrees' WFS1 mutations are frequently located in exon 4, this finding is very infrequent in other pedigrees, particularly in Italian patients. Conclusions: a) our report of two siblings with one novel WSF1 mutation (G107R) expands the molecular spectrum of WS; b) this is the 3rd report of Italian patients harbouring one mutation outside exon 8 and the 2nd with one mutation in exon 4; c) on the basis of the present observations, and literature data we can infer that mutation locations outside exon 8 do not seem to be clearly associated with peculiar phenotype expressions of WFS1 gene.     

Familial apolipoprotein CII deficiency: A preliminary analysis of the gene defect in two independent families

Summary We have used a cDNA clone for human apolipoprotein CII (apo CII) to study the apo CII genes in two independent individuals with familial apo CII deficiency. With all the restriction enzymes so far used, gene fragments hybridising with apo CII cDNA are observed that are indistinguishable from normal samples. This demonstrates that in neither of these individuals is the defect due to a major deletion of DNA in or around the apo CII gene. We have used a common polymorphism of the apo CII gene detected with the enzyme TaqI to follow the inheritance of the gene in the families of these apo CII deficient individuals. The pattern of inheritance that we observe is consistent with the defect causing apo CII deficiency being in, or closely linked to the apo CII structural gene.     

Elucidation of the gene defect in Marfan syndrome. Success by two complementary research strategies.

Marfan syndrome, which is characterized by manifestations in the skeletal, ocular and cardiovascular systems, is one of the most common inherited connective-tissue disorders. The independently performed genetic assignment of the Marfan locus and classical biochemical and immunohistochemical analyses complemented each other in the search for the Marfan gene defect and in 1991 the fibrillin gene in chromosome 15 was identified as the Marfan gene. So far, three mutations leading to the Marfan phenotype have been reported in this gene coding for a microfibrillar protein. The available data suggests a wide spectrum of different mutations of fibrillin and although mutations of the fibrillin gene account for the majority of Marfan cases, evidence also exists for locus heterogeneity in a minority of Marfan cases.