Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus

Abstract

We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…4,12,13,17,18,24,25,33 PCR products were Figure 2 Diagnostic flowchart for evaluation of a new CL patient with suspected autosomal recessive inheritance (non-type 1). The facial features of PYCR1, ALDH18A1 and GORAB-related syndromes are similar to each other and different from the ATP6V0A2-related ARCL2A.…”

“…XLCL is caused by mutations in ATP7A, a copper transporter gene. 3,4 Diagnosis can be made based on clinical features, low serum levels of copper and ceruloplasmin and mutation analysis. 3,4 In autosomal dominant CL (MIM 123700), the family history, the appearance of skin signs and organ involvement is variable.…”

The Mild Form of Menkes Disease: A 34 Year Progress Report on the Original Case

“…A more affected phenotype with prolonged survival comes from the family in which the responsible gene was cloned. These patients demonstrated various abnormalities across the spectrum of Menkes disease and Occipital Horn syndrome, with the 18 year old proband having mild intellectual disability, pili torti, bladder diverticuli, seizures, intracerebral haemorrhage, cutis laxa, vascular tortuosity, ataxia, occipital horns, scoliosis, pectus and multiple joint dislocations (Kaler et al 1994;Proud et al 1996).…”

“…Menkes disease and the occipital horn syndrome are disorders at either ends of a spectrum caused by mutations in the copper-transporting ATPase ATP7A gene (OMIM #300011) (Kaler et al 1994;Tumer et al 1997). Additionally, specific mutations in ATP7A cause a distal motor neuropathy that is clinically distinct (Kennerson et al 2010).…”

Nuclear proteins that bind to metal response element a (MREa) in the Wilson disease gene promoter are Ku autoantigens and the Ku‐80 subunit is necessary for basal transcription of the WD gene

“…Hepatic cirrhosis and neuronal degeneration are the most debilitating symptoms of WD and are caused by the impairment of biliary copper excretion and the accumulation of toxic concentration of copper. The WD gene product shares a high degree of sequence similarity with the cation-transporting P-type ATPases [1][2][3][4][5] and functions in the binding and translocation of copper [6].Interestingly, multiple copies of metal-response elements (MREs) are located in the 1.3-kb promoter of the WD gene [7]. Five or more nonidentical MREs are present in the 5¢-flanking region of the vertebrate metallothionein (MT) gene [8,9] and are believed to mediate the transcriptional activation of the MT gene by heavy metals [8,[10][11][12] and oxidative stress [13,14].…”