No abstract

Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.

X-linked mental retardation (XLMR) affects one in 600 males and is highly heterogeneous. We describe here a 29-year-old woman with severe nonsyndromic mental retardation and a balanced reciprocal translocation between chromosomes X and 15 [46,XX,t(X;15)(q13.3;cen)]. Methylation studies showed a 100% skewed X-inactivation in patient-derived lymphocytes indicating that the normal chromosome X is retained inactive. Physical mapping of the breakpoints localised the Xq13.3 breakpoint to within 3.9 kb of the first exon of the ZDHHC15 gene encoding a zinc-finger and a DHHC domain containing product. Expression analysis revealed that different transcript variants of the gene are expressed in brain. ZDHHC15-specific RT-PCR analysis on lymphocytes from the patient revealed an absence of ZDHHC15 transcript variants, detected in control samples. We suggest that the absence of the ZDHHC15 transcripts in this patient contributes to her phenotype, and that the gene is a strong candidate for nonsyndromic XLMR.

SummaryFamilial cases of cerebral palsy were traced all over Sweden. Fortythree families were collected, in 30 of which the patients were siblings. The families were divided into three groups: (1) 16 families with cases of identical syndromes and a history of normal pregnancy, delivery and perinatal period; (2) 3 families with cases of identical syndromes but an abnormal perinatal period; (3) 24 families with non‐identical syndromes.Within the first group, which is of main genetic importance, 10 families were found with 2‐3 siblings affected with congenital non‐progressive ataxia and mental retardation, the mode of inheritance with all probability being autosomal recessive. Three families showed ataxic diplegia, two of them only in siblings, the third with affected members of both sexes represented in three generations. Surprisingly enough, pure spastic diplegia was only revealed in one family, viz. a grandfather and his grandson. Spastic tetraplegia was found in two mentally retarded siblings in an otherwise healthy sibship of 11 members. True microcephaly combined with a dystonic tetraplegic cerebral palsy was seen in one family and was thought to have an autosomal recessive inheritance as in similar cases reported in the literature.Chromosome studies and laboratory screening tests revealed no abnormalities indicating particular aetiological mechanisms.

In a unselected series of children born in 1959--70 with severe mental retardation (MR)---defined as IQ less than 50---in a Swedish county, the incidence, prevalence, gestational length, birth weight and associated CNS handicaps were analysed. The cumulative incidence at 1-16 years of age was calculated at 3.3% and the prevalence at 11-16 years at 2.8%. These figures were lower than in most other previous studies. In the great majority of cases the pathogenesis was of prenatal origin. The mean gestational lengths and birth weights were decreased compared with those of an average Swedish population. Severe MR affected large and small for date babies more often than could be expected. On the other hand, babies, with a low birth weight, appropriate for gestational age, and with an uncomplicated history, were found not to run a special risk of severe MR. Among the 122 children, 42% had one or more associated CNS handicaps---epilepsy (30%) and cerebral palsy (18%) being the most common.