Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings

Y. Miyoshi, M. Akagi, A. K. Agarwal, N. Namba, K. Kato-Nishimura, I. Mohri, M. Yamagata, S. Nakajima, S. Mushiake, M. Shima, R. J. Auchus, M. Taniike, A. Garg, K. Ozono

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients'cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

Original languageEnglish (US)
Pages (from-to)535-544
Number of pages10
JournalClinical Genetics
Volume73
Issue number6
DOIs
StatePublished - Jun 2008

Fingerprint

Lamin Type A
Lipodystrophy
Siblings
Mutation
Exons
Acro-Osteolysis
Cranial Sutures
Clavicle
Skin
Metalloproteases
Missense Mutation
Thigh
Abdomen
Fluorescent Antibody Technique
Zinc
Thorax
Yeasts
Parents
Staining and Labeling
Phenotype

Keywords

  • Lamin A
  • Lipodystrophy
  • Mandibuloacral dysplasia
  • Progeroid syndrome
  • ZMPSTE24

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. / Miyoshi, Y.; Akagi, M.; Agarwal, A. K.; Namba, N.; Kato-Nishimura, K.; Mohri, I.; Yamagata, M.; Nakajima, S.; Mushiake, S.; Shima, M.; Auchus, R. J.; Taniike, M.; Garg, A.; Ozono, K.

In: Clinical Genetics, Vol. 73, No. 6, 06.2008, p. 535-544.

Research output: Contribution to journalArticle

Miyoshi, Y, Akagi, M, Agarwal, AK, Namba, N, Kato-Nishimura, K, Mohri, I, Yamagata, M, Nakajima, S, Mushiake, S, Shima, M, Auchus, RJ, Taniike, M, Garg, A & Ozono, K 2008, 'Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings', Clinical Genetics, vol. 73, no. 6, pp. 535-544. https://doi.org/10.1111/j.1399-0004.2008.00992.x
Miyoshi, Y. ; Akagi, M. ; Agarwal, A. K. ; Namba, N. ; Kato-Nishimura, K. ; Mohri, I. ; Yamagata, M. ; Nakajima, S. ; Mushiake, S. ; Shima, M. ; Auchus, R. J. ; Taniike, M. ; Garg, A. ; Ozono, K. / Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. In: Clinical Genetics. 2008 ; Vol. 73, No. 6. pp. 535-544.
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abstract = "Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients'cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.",
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AU - Miyoshi, Y.

AU - Akagi, M.

AU - Agarwal, A. K.

AU - Namba, N.

AU - Kato-Nishimura, K.

AU - Mohri, I.

AU - Yamagata, M.

AU - Nakajima, S.

AU - Mushiake, S.

AU - Shima, M.

AU - Auchus, R. J.

AU - Taniike, M.

AU - Garg, A.

AU - Ozono, K.

PY - 2008/6

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N2 - Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients'cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

AB - Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients'cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.

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