A splice site mutation confirms the role of LPIN2 in Majeed syndrome

Abstract

Majeed syndrome is an autoinflammatory disorder consisting of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis. To date, 2 unrelated families with Majeed syndrome have been reported. Mutations in LPIN2 have been found in both families. Here we report a third consanguineous family with Majeed syndrome with a novel mutation. The patient, a 3-year-old Arabic girl, had hepatosplenomegaly and anemia as a neonate. At age 15 months, she developed recurrent episodes of fever and multifocal osteomyelitis. In addition, bone marrow aspiration demonstrated significant dyserythropoiesis, suggesting Majeed syndrome. Coding sequences and splice sites of LPIN2 were sequenced in the patient and her mother. A homozygous single-basepair change was detected in the donor splice site of exon 17 (c.2327؉1G>C) in the patient; her mother was heterozygous at this site. These data confirm the role of LPIN2 mutations in the etiology of Majeed syndrome.

Chronic Recurrent Multifocal Osteomyelitis: Treatment with a Tumor Necrosis Factor-Alpha Inhibitor

“…[1] They are recurrent in nature [4] and are often associated with comorbid inflammatory disorders. [1,2,4,7] Involvement of other organs has been reported; [8,9] however, in this case, the simultaneous bouts of pain were restricted to multiple bone locations: the pelvis, clavicle, vertebrae, and both legs. Eighty-five percent of the CRMO cases have occurred in girls with a median onset age of 10 years old.…”

“…It is known that infections, immune deficiency, and autoimmunity are unlikely causes. The similarity with Majeed syndrome, an autosomal disorder, [4] and chronic multifocal osteomyelitis (CMO) in mice, [5] suggests a genetic origin. Mutations in LPIN2 cause a syndromic form of CRMO, and mutations in proline-serinethreonine phosphatase interacting protein 2 (PSTPIP2) cause a murine form of the disorder.…”

“…Mutations in LPIN2 cause a syndromic form of CRMO, and mutations in proline-serinethreonine phosphatase interacting protein 2 (PSTPIP2) cause a murine form of the disorder. [4,5] It is unclear how best to manage CRMO as there have been few randomized trials. Non-steroidal antiinflammatory drugs (NSAIDs) are considered to be the first line of therapy.…”

A Conserved Serine Residue Is Required for the Phosphatidate Phosphatase Activity but Not the Transcriptional Coactivator Functions of Lipin-1 and Lipin-2

“…In one family, deletion of two nucleotides in the lipin-2 coding region leads to a premature stop codon in the first third of the protein (20), likely resulting in nonsense-mediated mRNA decay and no functional protein product. A second mutation occurs in the donor splice site for exon 17 of the LPIN2 gene, which leads to readthrough of intron sequences adding 65 irrelevant amino acid residues before reaching a stop codon (21). Although both of these mutations would prevent production of full-length lipin-2 protein, the third known mutation is a point mutation that leads to a single amino acid substitution, S734L (20).…”

Autoinflammatory diseases and the inflammasome: mechanisms of IL-1β activation leading to neutrophil-rich skin disorders

“…Majeed syndrome has only been reported in Jordan and is caused by mutations in LPIN2 [28][29] . This rare disease is defined by an association of CRMO with congenital dyserythropoietic anemia and neutrophilic dermatosis, although the role of lipin 2 in bone and skin-localized inflammation remains unknown.…”