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Mutations in the Y-located testis-determining gene SRY are one cause for XY sex reversal. We have previously identified four SRY mutations in a total of 45 sex-reversed females with XY gonadal dysgenesis (XY GD). In a new sample of 16 XY GD cases, three previously undescribed SRY mutations were identified. Two are point mutations that lead to amino acid substitutions in the HMG domain of SRY, M64R, and F67V. The third SRY mutation is a single base insertion 5′ to the HMG box within codon 43, converting this lysine codon to a stop codon (K43X). A total of 33 SRY mutations have so far been described that account for only 10–15% of XY GD females. A further 10–15% of these cases result from deletion of SRY due to aberrant X/Y interchange. The etiology of the remaining 70–80% of XY GD cases is still enigmatic. Possible explanations for these XY sex-reversal cases are discussed.

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We have studied the structure and metabolism of type I procollagen in a case of perinatal lethal osteogenesis imperfecta (OI) type II. Cultured skin fibroblasts from the proband synthesized both normal and abnormal forms of type I procollagen. Some abnormal, overmodified molecules were secreted by OI cells, although less efficiently than normal molecules from control cells. The OI fibroblasts accumulated large amounts of abnormal proa1(I) and proa2(I) chains intracellularly. The extracellular collagenolytic activity was decreased compared to control cells. Furthermore, OI cells produced less type I procollagen and demonstrated lower capacity to synthesize DNA than control cells. We have found that in contrast to prolinase activity, the activity of prolidase (an enzyme essential for collagen synthesis and cell growth) is also significantly reduced in OI cells. No differences were found in the amount of the enzyme protein recovered from both the OI and control cells. However, we found that expressions of b1 integrin and insulin-like growth factor-I receptor (receptors known to play an important role in up regulation of prolidase activity) were decreased in OI cells compared to control cells. The decrease in prolidase activity may provide an important mechanism of altered cell growth and collagen metabolism involved in producing the perinatal lethal form of the OI phenotype.Keywords: collagen; prolidase; osteogenesis imperfecta.Osteogenesis imperfecta (OI) is an autosomal dominant disorder associated with defects in the synthesis or structure of type I collagen, the major protein of bone and skin [1,2]. It is a heterogeneous disease with variable clinical manifestations including multiple fractures, deafness, blue sclerae, laxity of joints and dentinogenesis imperfecta. The Sillence classification using radiographic and clinical criteria, defines four main types of OI [3]. The mildest and most common form is type I of OI, and the most severe form is the perinatal lethal type II.More than 90% of OI cases are due to heterozygosity for mutations in the structural genes for type I collagen: COL1A1 or COL1A2. The most common defects are point mutations with the remainder comprising null alleles, exon skipping, deletions, insertions and frameshift mutations.Mutations that produce only quantitative decrease in the synthesis of type I procollagen result in a mild OI phenotype [4,5]. More severe OI phenotypes are due to mutations that result in the synthesis and secretion of structurally abnormal type I procollagen into the extracellular matrix [6,7].The structural defects result in abnormalities of collagen metabolism including: delayed or defective self-assembly of procollagen heterotrimers [8,9], post-translational overmodification of lysine and hydroxylysine residues [10,11], decreased thermal stability of procollagen trimers [12,13], increased susceptibility of trimers to specific proteases [13], decreased secretion of procollagen by skin fibroblasts [14] and defective extracellular processing of type I procollagen [15...

We performed the segregation analysis of a relatively large pedigree of t(7;13)(q34;q13) carriers together with the sperm karyotype analysis of the one carrier using a tri-color fluorescence in situ hybridization (FISH) method. The risk assessments for unfavorable pregnancy outcomes in a series of 36 pregnancies in eight reciprocal chromosome translocation (RCT) couples of carriers were estimated directly from a pedigree after ascertainment correction. The individual probability rate for unbalanced child was predicted according to Stengel-Rutkowski and co-workers. The unbalanced karyotypes in the form of monosomy 7q34-->qter and trisomy 13q13-->qter were detected among stillborn/early death newborns with holoprosencephaly (HPE), cyclopia and other malformations. Based on clinical description of unkaryotyped stillbirth progeny, it can be assumed that the phenotype distinctions were connected with the unbalanced karyotype from 2:2 segregation (monosomy 7q with trisomy 13q) and 3:1 segregation as interchange trisomy 13 (Patau syndrome). Probability rates for miscarriages, stillbirth/early death were 12.9 +/- 6% (4/31) and 29 +/- 8.2% (9/31), respectively. The results of the meiotic segregation pattern indicated the rate of unbalanced spermatozoa for about 60%, with the unusual high rate (29.4%) of 3:1 segregant (i.e., 13.4% of the tertiary segregation and 16% of the interchange segregation). Adjacent-1 segregation followed with 23.5% and adjacent-2 followed with 7.2% of analyzed spermatozoa. The high rate of unbalanced gametes in comparison to the number of stillborn/early death and miscarriages detected in pedigree suggests a strong selection against unbalanced chromosomal constitutions during fetal development. It corresponds to a very small probability rate (about 0.3%) of viable unbalanced progeny from 3:1 meiotic segregation predicted for maternal carriers. This knowledge can be used in genetic counseling of families with similar RCT ascertained in a different way.