OBJECTIVEMutation in the heavy chain micro (microHC) gene causes a rare type of autosomal recessive agammaglobulinemia. Here we report the molecular and clinical characterization of a compound heterozygous mutation in the microHC gene in a patient with autosomal recessive agammaglobulinemia firstly from China.

METHODA one-year and ten-month-old male patient and his parents were enrolled in this study. No mutation was found in BTK gene. The microHC gene of the patient and his parents were amplified by polymerase chain reaction (PCR) from genomic DNA. Reverse transcription polymerase chain reaction (RT-PCR) was used to amplify the microHC transcripts. Sequencing was performed directly on the PCR products bidirectionally.

RESULTSSince 8 months of age, the patient had had recurrent fever and persistent cough. He suffered an acute right hemiplegia at 11 months of age and swelling and pain of left hip joint and right knee joint at one year and eight months of age. Cerebrospinal fluid routine examination showed that total cell count was 18 x 10(6)/L [normal range (0 - 15) x 10(6)/L], leukocyte count 7 x 10(6)/L [(0 - 15) x 10(6)/L] and biochemical examination showed protein 0.14 g/L (0.15 - 0.45 g/L), glucose 4.68 mmol/L (2.44 - 4.44 mmol/L) and chloride 116.3 mmol/L (120 - 132 mmol/L). Mycobacterium bovis was identified negative by cerebrospinal fluid smear examination. No obvious abnormity was detected on skull CT examination. Hydrothorax examination showed that total cell count was 848 x 10(6)/L, leukocyte count 785 x 10(6)/L and protein 30.8 g/L (< 30 g/L). Poliovirus isolation from stool sample of the patient was negative. The serum immunoglobulin (Ig) profile was IgG 181 mg/L (normal range, 5.09 - 10.09 g/L); IgM 28.8 mg/dl (400 - 1260 mg/dl) and IgA 22 mg/dl (310 - 670 mg/dl), IgE 4.6 U/ml (normal range < 150 U/ml). There were no B-cells but normal percentage of T-cells (67%) and NK cells (32%) were present in the peripheral blood. The patient had a compound heterozygous mutation in the microHC gene:on one allele, there was an alternative splice site mutation in exon 4 (1956 G > A), for which the patient's father was a carrier. Whereas on the other allele, an insert mutation between 170 and 175 in exon 1 with a premature stop codon (170 - 175 insert C, L11fs60X) was identified, for which the patient's mother was a carrier. The insert mutation in exon 1 of microHC gene was firstly reported. To detect the effect of the splice site mutation in exon 4, microHC cDNA of the patient was amplified by semi-nested PCR. The PCR products were purified and sequenced directly. A 136 bp of intron 4 was found in the transcripts and only the secreted isoform with a missense substitution is present in the patient, while synthesis of the membrane isoform is completely abolished.

CONCLUSIONThis is the first case with autosomal recessive agammaglobulinemia with compound heterozygous mutation in the microHC gene reported from China. A novel mutation in exon 1 was found.