The effect of homozygous deletion of the BBOX1 and Fibin genes on carnitine level and acyl carnitine profile

Abstract

Background: Carnitine is a key molecule in energy metabolism that helps transport activated fatty acids into the mitochondria. Its homeostasis is achieved through oral intake, renal reabsorption and de novo biosynthesis. Unlike dietary intake and renal reabsorption, the importance of de novo biosynthesis pathway in carnitine homeostasis remains unclear, due to lack of animal models and description of a single patient defective in this pathway.

Case presentation: We identified by array comparative genomic hybridization a 42 months-old girl homozygote for a 221 Kb interstitial deletions at 11p14.2, that overlaps the genes encoding Fibin and butyrobetaine-gamma 2-oxoglutarate dioxygenase 1 (BBOX1), an enzyme essential for the biosynthesis of carnitine de novo. She presented microcephaly, speech delay, growth retardation and minor facial anomalies. The levels of almost all evaluated metabolites were normal. Her serum level of free carnitine was at the lower limit of the reference range, while her acylcarnitine to free carnitine ratio was normal.

Conclusions: We present an individual with a completely defective carnitine de novo biosynthesis. This condition results in mildly decreased free carnitine level, but not in clinical manifestations characteristic of carnitine deficiency disorders, suggesting that dietary carnitine intake and renal reabsorption are sufficient to carnitine homeostasis. Our results also demonstrate that haploinsufficiency of BBOX1 and/or Fibin is not associated with Primrose syndrome as previously suggested.

Figure 1

Proband’s facial (A) and ear (B) appearance.

Figure 2

Proband’s chromosome 11 genotype (A) NimblegenHuman CGH 3 × 720 K Whole-Genome Tiling array profile of proband’s chromosomes 11. The homozygously deleted segment is pinpointed by a red arrow (B) Chromosomal position (top, marked by red box) and extents (bottom, red rectangles) of the homozygote deletion identified in the proband (top) and the heterozygote deletion described in a patient affected by Primrose syndrome [17] (bottom) in the UCSC genome browser. Both rearrangements encompass the Fibin and BBOX1 genes (GENCODE genes indicated in blue at the bottom of the panel [19]). The positions of the amplimers used to confirm the array CGH results are indicated by ticks (153P2-153P4). (C) Relative DNA amount was quantified by QPCR at human chromosome 11 loci defined in panel (B) for the proband, her mother and father, as well as an unaffected control. Data from three amplification reactions are represented as mean ± S.D.