Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family

Devi, A. Radha Rama; Gopikrishna, Munimanda; Ratheesh, Raman; Savithri, Gorinabele R.; Swarnalata, G; Bashyam, Murali D.

doi:10.1007/s10038-006-0019-z

Cited by 22 publications

(10 citation statements)

References 12 publications

(11 reference statements)

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“…For family 11, two affected children had died due to suspected FD; the parents consented to be tested for presence of carrier ASAH1 mutations. Families 1 and 4 were described previously. Seven families harbored a homozygous mutation while four harbored compound heterozygous mutations; a total of 13 different mutations were detected including 11 missense, 1 splice and 1 polypyrimidine tract (PPT) deletion (Table ).…”

Section: Resultsmentioning

confidence: 99%

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Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

et al. 2013

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Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.

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Section: Resultsmentioning

confidence: 99%

“…Clinical details of each patient are given in Appendix S1, Supporting information. Isolation of genomic DNA from blood samples and mutation screening were performed as described earlier. Screening for proband 1 was performed on DNA isolated from stored umbilical cord using the Tissue DNAeasy kit (Qiagen, Hamburg, Germany).…”

Section: Methodsmentioning

confidence: 99%

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

et al. 2013

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“…The hoarseness develops as a result of accumulation of ceramide and development of nodules on the vocal cords. Devi et al34 described a neonate who presented at the age of 1 month with hoarseness.…”

Section: Frequent Clinical Manifestations In the Neonatal Periodmentioning

confidence: 99%

Lysosomal Storage Disorders in the Newborn

et al. 2009

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Lysosomal storage disorders are rare inborn errors of metabolism, with a combined incidence of 1 in 1500 to 7000 live births. These relatively rare disorders are seldom considered when evaluating a sick newborn. A significant number of the >50 different lysosomal storage disorders, however, do manifest in the neonatal period and should be part of the differential diagnosis of several perinatal phenotypes. We review the earliest clinical features, diagnostic tests, and treatment options for lysosomal storage disorders that can present in the newborn. Although many of the lysosomal storage disorders are characterized by a range in phenotypes, the focus of this review is on the specific symptoms and clinical findings that present in the perinatal period, including neurologic, respiratory, endocrine, and cardiovascular manifestations, dysmorphic features, hepatosplenomegaly, skin or ocular involvement, and hydrops fetalis/congenital ascites. A greater awareness of these features may help to reduce misdiagnosis and promote the early detection of lysosomal storage disorders. Implementing therapy at the earliest stage possible is crucial for several of the lysosomal storage disorders; hence, an early appreciation of these disorders by physicians who treat newborns is essential. Keywordslysosomal storage disorders; neonatal; hydrops; enzyme deficiency THE LYSOSOMAL STORAGE disorders (LSDs) are rare diseases with a combined incidence of ~1 in 1500 to 7000 live births. 1,2 LSDs result from the inherited deficiency of 1 or more of the many catabolic enzymes that are located within the lysosome. This group of inborn errors of metabolism encompasses >50 different diseases, each characterized by the accumulation of specific substrates. [3][4][5][6] There are many steps necessary for the synthesis and processing of lysosomal enzymes, which makes this system prone to dysfunctions that can result from different mechanisms and at many different steps in the pathway.LSDs classically have not been considered disorders of the newborn. Generally, clinicians are taught that newborns with LSDs appear normal at birth and that the symptoms develop progressively over the first few months of life or even after many years. However, a portion

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“…Typical symptoms include painful swelling of joints, hoarseness, and premature death, and depending on the tissues affected by the storage of ceramides, severe nervous system dysfunction (Moser 1995). Several mutations for Farber disease have been reported; a single nucleotide deletion (V96del, Muramatsu et al 2002) and nine single nonsynonymous mutations (Y36C, V97E, E138V, L182V, T222K, G235R, R254G, N320D, and P362R, Koch et al 1996;Li et al 1999;Bär et al 2001;Muramatsu et al 2002;Devi et al 2006). The gene is located on the short arm of chromosome 8 (8p22-p21.3), is $28.5 kb long, appears to be a single-copy gene, and encodes 14 exons.…”

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confidence: 99%

Population Genetic Analysis of the N-Acylsphingosine Amidohydrolase Gene Associated With Mental Activity in Humans

Kim

Satta

2008

Genetics

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To understand the evolution of human mental activity, we performed population genetic analyses of nucleotide sequences ($11 kb) from a worldwide sample of 60 chromosomes of the N-acylsphingosine amidohydrolase (ASAH1) gene. ASAH1 hydrolyzes ceramides and regulates neuronal development, and its deficiency often results in mental retardation. In the region ($4.4 kb) encompassing exons 3 and 4 of this gene, two distinct lineages (V and M) have been segregating in the human population for 2.4 6 0.4 million years (MY). The persistence of these two lineages is attributed to ancient population structure of humans in Africa. However, all haplotypes belonging to the V lineage exhibit strong linkage disequilibrium, a high frequency (62%), and small nucleotide diversity (p ¼ 0.05%). These features indicate a signature of positive Darwinian selection for the V lineage. Compared with the orthologs in mammals and birds, it is only Val at amino acid site 72 that is found exclusively in the V lineage in humans, suggesting that this Val is a likely target of positive selection. Computer simulation confirms that demographic models of modern humans except for the ancient population structure cannot explain the presence of two distinct lineages, and neutrality is incompatible with the observed small genetic variation of the V lineage at ASAH1. On the basis of the above observations, it is argued that positive selection is possibly operating on ASAH1 in the modern human population.

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Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family

Cited by 22 publications

References 12 publications

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Lysosomal Storage Disorders in the Newborn

Population Genetic Analysis of the N-Acylsphingosine Amidohydrolase Gene Associated With Mental Activity in Humans

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