Autosomal Recessive Mutations

PC C56 C56.002 DJ-1 putative peptidase Mutations in the gene cause PARK7, an autosomal recessive form of early-on set parkinsonism... 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

This benign autosomal recessive disorder consists of conjugated hyperbilirubinemia in childhood or during adult life. The hyperbilirubinemia is caused by mutations in the gene encoding MRP-2 (see above), the protein involved in the secretion of conjugated bilirubin into bile. The centrilobular hepatocytes contain an abnormal black pigment that may be derived from epinephrine. 

Figure 52-7. Simplified scheme of the sequence of events involved in the causation of chronic granulomatous disease (MIM 306400). Mutations in any of the genes for the four polypeptides involved (two are components of cytochrome b55gand two are derived from the cytoplasm) can cause the disease. The polypeptide of 91 kDa is encoded by a gene in the X chromosome approximately 60% of cases of chronic granulomatous disease are X-linked, with the remainder being inherited in an autosomal recessive fashion.

Acatalasemia is a rare hereditary deficiency of tissue catalase and is inherited as an autosomal recessive trait (03). This enzyme deficiency was discovered in 1948 by Takahara and Miyamoto (Tl). Two different types of acatalasemia can be distinguished clinically and biochemically. The severe form, Japanese-type acatalasemia, is characterized by nearly total loss of catalase activity in the red blood cells and is often associated with an ulcerating lesion of the oral cavity. The asymptomatic Swiss-type acatalasemia is characterized by residual catalase activity with aberrant biochemical properties. In four unrelated families with Japanese-type acatalasemia, a splicing mutation due to a G-to-A transition at the fifth nucleotide in intron 4 was elucidated (K20, W5). We have also determined a single base deletion resulting in the frameshift and premature translational termination in the Japanese patient (HI6). 

Carbonic anhydrase (CA) exists in three known soluble forms in humans. All three isozymes (CA I, CA II, and CA III) are monomeric, zinc metalloenzymes with a molecular weight of approximately 29,000. The enzymes catalyze the reaction for the reversible hydration of C02. The CA I deficiency is known to cause renal tubular acidosis and nerve deafness. Deficiency of CA II produces osteopetrosis, renal tubular acidosis, and cerebral calcification. More than 40 CA II-defi-cient patients with a wide variety of ethnic origins have been reported. Both syndromes are autosomal recessive disorders. Enzymatic confirmation can be made by quantitating the CA I and CA II levels in red blood cells. Normally, CA I and CAII each contribute about 50% of the total activity, and the CAI activity is completely abolished by the addition of sodium iodide in the assay system (S22). The cDNA and genomic DNA for human CA I and II have been isolated and sequenced (B34, M33, V9). Structural gene mutations, such as missense mutation, nonsense... 

Ying L, Katz Y, Schlesinger M et al. Complement factor H gene mutation associated with autosomal recessive-atypical hemolytic uremic syndrome. Am J Hum Genet 1999 65[6] 1538—1546. 

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

Birouk, N., Azzedine, H., Dubourg, O. et al. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Arch. Neurol. 60 598-604,2003. 

Kitada, T., Asakawa, S., Hattori, N. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392 605-608,1998. 

Bonifati, V., Rizzu, P., van Baren, M. J. etal. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299 256-259, 2003. 

Primary lysosomal hydrolase defects. Two-thirds of the lysosomal storage diseases involve defects in genes that code for acid hydrolases. Table 41-2 lists 29 defects that have been defined so far. They have an autosomal recessive mode of inheritance, except for Hunter s syndrome and Fabry s disease, where the mode is X-linked recessive. The defective genes have been identified and mutations have been defined for nearly all. The nervous system is involved in most. Many of the disorders show a wide range of clinical severity, which may range from death in early childhood to a moderate disability in adulthood. 

Amyotrophic lateral sclerosis 2 is linked to mutant alsin. In several families with autosomal recessive juvenile ALS, mutations have been identified in ALS2 (chromosome 2), encoding alsin [65, 66], This illness, which was originally described in a Tunisian kindred, is characterized by spasticity (involvement of upper motor neurons) and weakness/amyotrophy (involvement of lower... 

Mutant Tbce mice. Progressive motor neuropathy (PMN), an autosomal recessive murine disease, manifests as weakness beginning within a few weeks of birth [14, 136]. These mice are homozygous for a Trp 524 Gly substitution of Tbce (tubulin-specific chaperone E), localized to mouse chromosome 13 [14]. Tbce mRNA is present in neurons in the spinal cord. Degenerative changes are conspicuous in motor axons, and ultrastructural studies of peripheral nerves of PMN mice disclose reduced numbers of microtubules in these axons. Mutations of the highly conserved Trp524 residue, which appears to influence... 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

Mutations in rhodopsin and other photoreceptor proteins are linked to retinitis pigmentosa. Retinitis pigmentosa (RP) is a group of inherited retinopathies that affects about 1 in 4,000 humans [26], RP maybe classified into four types autosomal dominant (19%), autosomal recessive (19%),X-linked (8%) and allied diseases (54%). RP is characterized by loss of night vision in the early stage, followed by loss of peripheral vision. Chromosomal loci for numerous RP genes have been mapped and mutations characterized [27]. 

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