Human mutation
-
Mutations in each of the 13 identified human PEX genes are known to cause a peroxisomal biogenesis defect (PBD). Affected patients can be divided into two broad clinical spectra: the Zellweger spectrum, which accounts for about 80% of PBD patients, and the rhizomelia chondrodysplasia punctata (RCDP) spectrum. The clinical continuum of Zellweger spectrum patients extends from Zellweger syndrome (ZS) as the prototype and the most severe entity of this group to neonatal adrenoleukodystrophy (NALD) as an intermediate form and infantile Refsum (IRD) disease as the mildest variant. ⋯ Similar but less severe clinical signs are seen in patients with NALD and IRD. In this study ten clinically and/or biochemically well-characterized patients with classical ZS were investigated for defects in all known human PEX genes. We identified two novel mutations in PEX2 (official symbol, PXMP3), two novel mutations in PEX6, two novel mutations in PEX10, one novel mutation in PEX12, and one novel mutation in PEX13.
-
The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. ⋯ In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype-phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions.
-
Hyperekplexia (startle disease) is a hereditary motor disease caused by mutations within the GLRA1 gene (Chr. 5q33.1), which encodes the alpha1 subunit of the inhibitory glycine receptor (GlyR). While most patients are diagnosed with dominant hyperekplexia associated with point mutations within or adjacent to the channel pore, recessive hyperekplexia is less frequent. Here, we report five new pedigrees of recessive hyperekplexia in apparently unrelated families of Kurdish origin associated with a deletion of exons 1-7 of the GLRA1 gene. ⋯ Consensus sites for Toposiomerase II were detected close to the breakpoint compatible with an illegitimate recombination event. No heterozygous carriers of the deletion allele were detected by screening of 500 individuals from the southeastern Mediterranean region belonging to four different ethnic groups. Hence, the identical nature of the breakpoint junction in all patients and carriers suggests a founder mutation in an ethnic population originating from Turkey.
-
Members of the caspase family can be important for apoptosis or inflammation, but the role of caspase-12 (CASP12 or CSP12) is unclear. Although most humans lack a functional caspase-12, the Csp 12-L variant, previously found only among people of African descent, produces a full-length proenzyme and increases the risk of sepsis. In this study, Csp 12-L allele frequency ranged from 3.6% to 60.7% among populations from sub-Saharan Africa and was also present at low frequency among North African, Middle Eastern, and South Asian populations.
-
Malignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. ⋯ Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.