Study of Hereditary Disorders in Pakistan Human Kindreds-II

Abstract

As a result of a country-wide search for families showing hereditary disorders, 6 such families have been located and studied as summarized below: Recently we have described a large unbred family from a remote area of Baluchistan with a distinct, recessively inherited form of spondyloepimetaphyseal dysplasia (SEMD; American Journal of Medical Genetics 78:468-473,1998). This newly described entity, termed SEMD Pakistani type, is characterized by short, bowed lower limbs, enlarged knee joints, kyphoscoliosis, a mild generalized brachydactyly, irregularity of the epiphyses and metaphyses, delayed epiphyseal ossification and platyspondyly. In a later publication (Nature Genetics 20:157-162,1998) typing a total of 381 microsatellite DNA markers, we localized the disease gene for SEMD Pakistani type to human chromosome 10q23-24, a region syntenic with the brachymorphic (bm) locus on mouse chromosome 19. Orthologous genes encoding a previously undescribed ATP sulfurylase/APS kinase enzyme were identified in the respective syntenic regions of the human and mouse genomes. A nonsense mutation and a missense mutation in these genes were defined as the underlying cause of the human SEMD and mouse brachymorphic phenotypes, respectively. A family from Gujranwala District has congenital generalized alopecia as a single abnormality without any associated defects, a condition distinct from congenital alopecia universalis. Analysis of the pedigree is suggestive of autosomal recessive inheritance, the parents of the affected sibship being first cousins and apparently normal. As our previous work has shown that the gene responsible for the isolated congenital universal alopecia in two Pakistani families maps to the short arm of the chromosome 8 (Science 279:720-724; 1998; American Journal of Human Genetic 62:386-390; 1998), the microsatellite markers D8S298, D8S1786 and D8S1739 known to be linked to the gene for alopecia universalis were used to check linkage to the same region of the chromosome 8. Haplotype analysis conclusively excluded linkage of the gene for generalized alopecia to the short arm of the chromosome 8. In addition, linkage to type I hair keratin gene cluster on chromosome 17q12-21 and type II hair keratin gene cluster on chromosome 12q11-13 were also excluded using DNA microsatellite markers known to be present in the vicinity of these gene clusters. The chromosome region 1q21 which contains a cluster of several epidermally expressed genes was also excluded. The markers at locus D18S36 provided evidence of close linkage of the disease locus to the chromosomal region, 18q12 (lod score of 3.92 at 0 recombination fraction). This chromosomal region i.e., 18q12 contains genes for desmosomal cadherins i.e., desmogleins (DSG1, DSG2, DSG3) and desmocollins (DSC1, DSC2, DSC3) along with a zinc finger gene ZNF 191. Screening of all these genes for mutation analysis by PCR amplification and direct sequencing of 15 exons from each failed to identify any mutation. Large inbred kindred from Swat showed acromesomelic dysplasia i.e., severe dwaefism with shortening of the extremities but normal trunk. As a result of clinical examination and X-rays, the condition was diagnosed as chondrodysplasia Grebe type. Analysis of the pedigree is strongly suggestive of autosomal recessive inheritance. The family has been compared with another Pakistani family from Sargodha with Du pan Syndrome previously described by the principal Investigator (American Journal of Medical Genetics 36:292-296;1990), and relationship between three types of chonderodysplasia i.e., Grebe type (CGT), Hunter and Thompson type (CHTT), and Du Pan Syndrome, has been discussed. DNA studies have been planned to work out molecular bases of these conditions. Two families, hereinafter designated as family A and family B, showing different types of autosomal recessive ectodermal dysplasia, have been studied. In family A, the affected person showed hypotrichosis, and dental, nail and skin abnormalities. As a result of clinical and histopathological examinations, the condition was diagnosed as hypohidrotic ectodermal dysplasia. As different types of ectodermal dysplasia have been shown to be linked to chromosomes X,13 and 2, using PCR and microsatellite DNA markers, an attempt was made to confirm or exclude linkage of ectodermal dysplasia in the Family A to any of the above-given chromosomal regions. The results showed that the gene for ectodermal dysplasia in this family is not linked to any of the known chromosomal regions given above. A genome-wide search to localize and identify the gene and to define the mutation causing this disorder is continuing. The disorder in family B, as a result of clinical examination and histopathology of the affected persons, was diagnosed as hidrotic ectodermal dysplasia, with abnormal nails and skins, but the hair and teeth were normal. The pedigree is compatible with autosomal recessive mode of inheritance. Using PCR and microsatellite DNA markers, further research will be carried out on the same lines as in the case of family A. A family from Dera Ghazi Khan showing dyschondrosteosis has also been studied, but not included in this report. The family being highly inbred, the pedigree can be explained both by autosomal recessive, and autosomal dominant with incomplete penetrance, modes of inheritance. Out of 11 affected persons, 2 were males and 9 females. In families showing dyschondrosteosis or Madelung deformity, preponderance of affected females has also previously been noted. Also, females are more severely affected than males. Thus, preponderance of affected females may be either a peculiarity of genetics of this trait or merely an ascertainment bias. The affected persons are normal with respect to intelligence, crainiofacies and axial skeleton with moderate reduction in stature (mesomelic dwarfism) and variable expression of the trait. In brief, the X-rays of the affected persons showed bilateral shortening and bowing of radius and ulna, subluxation of wrist and elbow joints due to hypoplastic ends of these bones. The carpal bones are misaligned. The lower limbs show slight shortening of fibula at the proximal end, its proximal head not articulating with lateral tibial condyle. DNA studies will be conducted to determine if this condition is due to the already known locus for dyschondrosteosis or there is locus heterogeneity.